Pharmaceutical composition and method of manufacturing

ABSTRACT

The present invention provides for methods of obtaining an extract of Cannabis plant material as well as subsequent processing of the extract to provide a concentrate of Cannabis. The present invention also provides for pharmaceutical dosage forms (e.g., oral thin films and transdermal patches) that include the concentrate (or extract) of Cannabis, as well as methods of medical treatment that include administering the pharmaceutical dosage forms.

CLAIM OF PRIORITY

This patent application is a Continuation of U.S. patent applicationSer. No. 14/255,296, filed Apr. 17, 2014, and is incorporated byreference herein.

BACKGROUND

The medicinal and psychoactive properties of the Cannabis plant havebeen known for centuries. At present, Cannabis is not legally availablein many States. However, there is growing pressure on politicians tolegalize its use, especially for medicinal purposes.

Evidence suggests that Cannabis is a safe, versatile and potentiallyinexpensive drug. It has been reported as being beneficial to patientssuffering from a wide range of symptoms experienced in connection withvarious, often very serious, medical conditions. For example, Cannabishas been used to alleviate symptoms associated with cancer, anorexia,AIDS, chronic pain, spacicity, glaucoma, arthritis, migraine and manyother illnesses.

Cannabis is recognized as having anti-emetic properties and has beensuccessfully used to treat nausea and vomiting in cancer patientsundergoing chemotherapy.

Studies also report use of Cannabis in treating the weight loss syndromeof AIDS and in reducing intraocular pressure for the treatment ofglaucoma. Cannabis is also reported to have muscle relaxing effects andanti-convulsant effects.

However, it is also well documented that these medicinal effects ofCannabis come at the cost of less desirable effects. It is alleged thatthe administration of Cannabis causes changes in mood, perception andmotivation. The common euphoric effects have led to the use of Cannabisas a recreational, “soft” drug and its criminalization. The psychoactiveeffects are said to vary with dose, with the typical Cannabis smokerexperiencing a “high” which lasts about 2 hours, during which there isimpairment of cognitive functions, perception, reaction time, learningand memory. These side effects clearly have implications, such as forthe operation of machinery, and in particular for driving. These effectsalso make Cannabis less attractive for widespread, mainstream use, as itcan reduce a patient's ability to perform relatively simple tasks duringtreatment.

The euphoric effects of Cannabis may also constitute an undesirable sideeffect for patients using the drug for medicinal purposes, especiallyfor “naive” Cannabis users. Furthermore, here have been reports ofunpleasant reactions to Cannabis, such as anxiety, panic orhallucinations. It is believed that these undesirable effects are mostcommonly associated with higher doses of Cannabis.

Despite these effects, years of research have failed to show thatCannabis is dangerous. In fact, the results appear to have proved theopposite. Cannabis has been shown to be safer, with fewer serious sideeffects than most prescription drugs currently used as anti-emetics,muscle relaxants, hypnotics and analgesics, etc.

The physiological and pharmacological effects of Cannabis depend upon anumber of factors, including the dosage level and the route ofadministration.

There are currently two main methods of Cannabis delivery. Lung deliveryis most commonly achieved by smoking Cannabis. Unfortunately, there areconcerns about the effect of this mode of administration on the lungs.Cannabis smoke carries even more tars and other particulate matter thantobacco, and so may be a cause of lung cancer. Furthermore, manypatients find the act of smoking unappealing, as well as generallyunhealthy. It is known that some of the chemicals produced by smokingCannabis are aggressive and smoking has been shown to cause the gradualdissolving of teeth. Use of vaporizers for inhalation administration ofCannabis does not avoid the production of thermal byproducts, and alsocan produce tracheal and lung irritation. For these reasons, smoking isnot an approved medical means of administration for any drug.

Attempts have been made to overcome some of the problems associated withsmoking both Cannabis and tobacco by providing various smokelessinhalable aerosol formulations for lung delivery. A self-propelledinhalable aerosol of delta-9-tetrahydrocannabinol was developed as longago as 1975 as a bronchodilator. Inhalable aerosol formulations weremade comprising either only liquid components and or including a solidparticulate component carrying the active agent, such as the Cannabis.The various formulations were found to be of varying effectiveness indelivering the active agent to the alveoli of the lungs in the samemanner as smoke.

However, both methods of lung delivery discussed above have been foundto cause a pronounced and involuntary cough, possibly from irritation ofthe trachea and lungs. This unpleasant side effect is not overcome bythe smoke-free method of lung delivery.

An oral dosage form of Cannabis is available in the United States as aSchedule II drug. The capsules contain a synthetic version ofdelta-9-tetrahydrocannabinol (delta-9-THC), the main active substance inCannabis, and they have had limited success for a number of reasons.Firstly, in light of its anti-emetic properties, the capsules arecommonly used to treat nausea and vomiting. Clearly, an oraladministration is not ideal as the patient may well have difficultykeeping the capsule down long enough for it to take effect. It has alsobeen found that orally administered THC is erratically and slowlyabsorbed into the bloodstream, making the dose and duration of actiondifficult to control. Furthermore, the oral dose is less effective thansmoked Cannabis and therefore larger doses are required in order toachieve a desired therapeutic effect.

SUMMARY

The present invention provides for a process for obtaining an extract ofCannabis. The process includes: (a) contacting Cannabis plant materialwith a supercritical fluid solvent system at a pressure between about750 psi and 25,000 psi, and at a temperature between about −15° C. and200° C., to provide an extract of Cannabis; and (b) optionally removingthe supercritical fluid solvent system from the extract of Cannabis toprovide a concentrate of Cannabis.

The present invention provides for an additional process for obtainingan extract of Cannabis. The process includes: (a) contacting Cannabisplant material with a supercritical fluid solvent system at a pressurebetween about 750 psi and 25,000 psi, and at a temperature between about−15° C. and 200° C., to provide an extract of Cannabis and an extractedCannabis plant material; (b) removing the supercritical fluid solventsystem from the extract of Cannabis to provide a concentrate ofCannabis; (c) contacting the extracted Cannabis plant material with asecond supercritical fluid solvent system at a pressure between about750 psi and 25,000 psi, and at a temperature between about −15° C. and200° C., to provide a second extract of Cannabis and a second extractedCannabis plant material; and (d) optionally removing the secondsupercritical fluid solvent system from the second extract of Cannabisto provide a second concentrate of Cannabis.

The present invention provides for an additional process for obtainingan extract of Cannabis. The process includes: (a) contacting Cannabisplant material with a supercritical fluid solvent system at a pressurebetween about 750 psi and 25,000 psi, and at a temperature between about−15° C. and 200° C., to provide an extract of Cannabis and an extractedCannabis plant material; (b) removing the supercritical fluid solventsystem from the extract of Cannabis to provide a concentrate ofCannabis; (c) contacting the extracted Cannabis plant material with asecond supercritical fluid solvent system at a pressure between about750 psi and 25,000 psi, and at a temperature between about −15° C. and200° C., to provide a second extract of Cannabis and a second extractedCannabis plant material; (d) removing the second supercritical fluidsolvent system from the second extract of Cannabis to provide a secondconcentrate of Cannabis; (e) contacting the second extracted Cannabisplant material with a third supercritical fluid solvent system at apressure between about 750 psi and 25,000 psi, and at a temperaturebetween about −15° C. and 200° C., to provide a third extract ofCannabis and a third extracted Cannabis plant material; and (f)optionally removing the third supercritical fluid solvent system fromthe third extract of Cannabis to provide a third concentrate ofCannabis.

The present invention provides for an additional process for obtainingan extract of Cannabis. The process includes: (a) contacting Cannabisplant material with a supercritical fluid solvent system at a pressurebetween about 750 psi and 25,000 psi, and at a temperature between about−15° C. and 200° C., to provide an extract of Cannabis and an extractedCannabis plant material; (b) removing the supercritical fluid solventsystem from the extract of Cannabis to provide a concentrate ofCannabis; (c) contacting the extracted Cannabis plant material with asecond supercritical fluid solvent system at a pressure between about750 psi and 25,000 psi, and at a temperature between about −15° C. and200° C., to provide a second extract of Cannabis and a second extractedCannabis plant material; (d) removing the second supercritical fluidsolvent system from the second extract of Cannabis to provide a secondconcentrate of Cannabis; (e) contacting the second extracted Cannabisplant material with a third supercritical fluid solvent system at apressure between about 750 psi and 25,000 psi, and at a temperaturebetween about −15° C. and 200° C., to provide a third extract ofCannabis and a third extracted Cannabis plant material; (f) removing thethird supercritical fluid solvent system from the third extract ofCannabis to provide a third concentrate of Cannabis; (g) contacting thethird extracted Cannabis plant material with a fourth supercriticalfluid solvent system at a pressure between about 750 psi and 25,000 psi,and at a temperature between about −15° C. and 200° C., to provide afourth extract of Cannabis and a fourth extracted Cannabis plantmaterial; and (h) optionally removing the fourth supercritical fluidsolvent system from the fourth extract of Cannabis to provide a fourthconcentrate of Cannabis.

The present invention provides for an additional process for obtaining aconcentrate of Cannabis. The process includes: (a) contacting Cannabisplant material with a supercritical fluid solvent system, at a pressurebetween about 750 psi and 25,000 psi, and at a temperature between about−15° C. and 200° C., to provide an extract of Cannabis; and (b) removingthe supercritical fluid solvent system from the extract. The (a)contacting of the Cannabis plant material with the supercritical fluidsolvent system and the (b) removing the supercritical fluid solventsystem, is carried out multiple times, such that the process may be afractional supercritical fluid extraction. Additionally, each contactingof the Cannabis plant material with a supercritical fluid solvent systemindependently occurs at a pressure between about 750 psi and 25,000 psi,and independently occurs at a temperature between about −15° C. and 200°C.

The present invention also provides a pharmaceutical dosage form, whichcan be an oral thin film (OTF) suitable for oral delivery, or anadhesive topical patch suitable for transdermal delivery. Thepharmaceutical dosage form includes a Cannabis concentrate including atleast one of cannabinol (CBN); cannabinolic acid (CBNA);Δ(9)-tetrahydrocannabinol (Δ(9)-THC); Δ(9)-tetrahydrocannabinolic acid(Δ(9)-THCA); Δ(9)-cannabidiol (Δ(9)-CBD); Δ(9)-tetrahydrocannabidiolicacid (Δ(9)-CBDA); Δ(8)-tetrahydrocannabinol (Δ(8)-THC);Δ(8)-tetrahydrocannabinolic acid (Δ(8)-THCA); Δ(8)-tetrahydrocannabidiol(Δ(8)-CBD); Δ(8)-tetrahydrocannabidiolic acid (Δ(8)-CBDA);Δ(9)-tetrahydrocannabivarin (Δ(9)-THV); cannabigerol (CBG);cannabigerolic acid (CBGA); cannabichromene (CBC); cannabichromenic acid(CBCA); cannabicyclol (CBL); cannabicyclolic acid (CBLA);β-caryophyllene epoxide; mentha-1,8(9)-dien-5-ol; pulegone; limonene;limonene oxide; α-terpinene; terpinen-4-ol; carvacrol; carvone;1,8-cineole; p-cymene; fenchone; pulegone-1,2epoxide; β-myrcene;cannaflavin A; and cannaflavin B.

The present invention provides a method of treating a mammal afflictedwith a disease or disorder. The method includes administering to amammal in need of such treatment, the pharmaceutical dosage formdescribed herein, in an amount and for a period of time, effective totreat the disease or disorder.

In various embodiments of the present invention, the methods ofmanufacturing described herein employ supercritical fluid extraction(SFE) to provide an extract of Cannabis. The solvent can conveniently beremoved from the extract, to provide a concentrate (or an essential) ofCannabis. When the SFE is a fractional supercritical fluid extraction(FSFE), the desired extract of Cannabis can include, e.g., cannabinoids,terpenoids, and/or flavonoids. In various embodiments, the desiredextract of Cannabis (relative to the starting plant material) will beenriched with the desired product (e.g. cannabinoids, terpenoids, and/orflavonoids). In further embodiments, the desired extract of Cannabis(relative to the undesired extract of Cannabis) will be enriched withthe desired product (e.g. cannabinoids, terpenoids, and/or flavonoids).In yet further embodiments, the undesired extract of Cannabis (relativeto the desired extract of Cannabis) will be enriched with the undesiredproduct (e.g. terpenes, alkaloids, hemp oil, and/or cannabinoid acids).As such, the FSFE can be employed to selectively obtain one or moredesired substances from the Cannabis plant material, while selectivelyexcluding one or more undesired substances.

In other embodiments, purified fractions enriched in certain of theCannabis components listed herein relative to other of the Cannabiscomponents, can be prepared by a method of the invention. For instance,fractions enriched in certain cannabinoids relative to othercannbinoids, compared to proportions as occurring in the Cannabis plantmaterial that is extracted, can be obtained by practice of a method ofthe invention. In this way, enriched purified fractions of Cannabisextract can be obtained, which can offer therapeutic benefits to apatient receiving treatment thereby.

While the concentrate (or essential oil) of Cannabis can conveniently beobtained from the desired extract of Cannabis upon removal of thesolvent, the concentrate, or a SFE-purified fraction thereof, cansubsequently be further purified by standard purification techniques.Alternatively, the concentrate, or a SFE-purified fraction thereof, or afurther purified fraction thereof, can be used directly in apharmaceutical dosage form (e.g., transdermal patch or oral thin film)without any further purification.

Transdermal patches typically include one or more adhesives positionedon the surface of the backing that contacts the user when used. TheCannabis concentrate, or a SFE-purified fraction thereof, or a furtherpurified fraction thereof, can conveniently be used directly in themanufacture of a transdermal patch, e.g., by mixing the concentrate withthe one or more adhesives. This will avoid the necessity to dissolve anyactive pharmaceutical ingredient in the adhesive layer of thetransdermal patch. This may also assist in avoiding issues that mayotherwise exist with a high load of desired compounds present inCannabis (e.g. cannabinoids, terpenoids, and/or flavonoids) in thetransdermal patch. The Cannabis concentrate can be used directly fromthe Cannabis extract (e.g., upon removal of the supercritical fluidsolvent), or alternatively can first be purified, e.g., by SFEfractionation, or by standard purification techniques, or by acombination thereof, and then employed in the manufacture of the topicalpatch.

Likewise, the manufacture of an oral thin film (OTF) typically includesthe casting and drying of a viscous liquid (or slurry). The Cannabisconcentrate, or a SFE-purified fraction thereof, or a further purifiedfraction thereof, can be used directly in the manufacture of an OTF,e.g., by mixing the concentrate with the viscous liquid. This will avoidthe necessity to dissolve any active pharmaceutical ingredient in theviscous liquid prior to drying. As such, the concentrate canconveniently be used directly in the manufacture of an OTF. This mayalso assist in avoiding issues that may otherwise exist with a high loadof desired compounds present in Cannabis (e.g. cannabinoids, terpenoids,and/or flavonoids) into an OTF. The Cannabis concentrate can be useddirectly from the Cannabis extract (e.g., upon removal of thesupercritical fluid solvent), or alternatively can first be purified,e.g., by SFE fractionation, or by standard purification techniques suchas chromatography, or by a combination thereof, and then employed in themanufacture of the OTF.

In specific embodiments, advantages of a transdermal drug delivery routeover other types of medication delivery such as oral, topical,intravenous, intramuscular, etc. is that the patch provides a controlledrelease of the medication into the patient, usually through either aporous membrane covering a reservoir of medication or through body heatmelting thin layers of medication embedded in the adhesive. The factthat the transdermal patch can provide a controlled release ofmedication for up to seven days gives it a major advantage over othertypes of drug delivery, such as oral or other types of topicaladministration (for example, gels or creams).

The delivery of a drug via a transdermal route of application can offerthe best of oral and intravenous administration. Avoidance of thefirst-pass effect leads to better bioavailability and may result infewer side effects. Consistent and controlled drug delivery avoidsperiods of under- and overdosing. Transdermal patches deliver drugs overa longer period of time, thus allowing for reduced dosing frequency. Atransdermal patch is administered by the patients themselves andadministration is stopped by removal of the patch. Contrary tointravenous drips or infusion pumps, patient activity is not restricted.These numerous benefits lead to significantly improved patientcompliance and as a consequence transdermal patches can offer a criticaledge to new and established drugs in competitive markets.

Both transdermal patches as well as oral thin films (OTFs) serve as analternative dosage form for patients who experience dysphagia(difficulty in swallowing). Additional reasons to use transdermalpatches and/or OTFs include the convenience of a dosage form that can betaken without water as well as the inability of the patient to eat ordrink (e.g., nausea and/or vomiting). Additional reasons to usetransdermal patches and/or OTFs with any substance derived from a plantmaterial that is typically inhaled, includes the avoidance of smoke andcarcinogenic constituents in the smoke, both with the primary user aswell as individuals in close proximity (e.g., second-hand smoke).

In specific embodiments, advantages of OTFs include the potential toimprove the onset of action, lower the dosing, and enhance the efficacyand safety profile of the medicament. All tablet dosage forms, softgelsand liquid formulations primarily enter the blood stream via thegastrointestinal tract, which subjects the drug to degradation fromstomach acid, bile, digestive enzymes and other first-pass effects. As aresult, such formulations often require higher doses and generally havea delayed onset of action. Conversely, buccal and sublingual OTF drugdelivery can avoid these issues and yield quicker onsets of action atlower doses.

In specific embodiments, advantages of OTFs include the thin film istypically more stable, durable and quicker dissolving than many otherconventional dosage forms.

In specific embodiments, advantages of OTFs include the thin filmenables improved dosing accuracy relative to liquid formulations sinceevery strip is manufactured to contain a precise amount of the drug.

In specific embodiments, advantages of OTFs include the thin film notonly ensures more accurate administration of drugs but also can improvecompliance due to the intuitive nature of the dosage form and itsinherent ease of administration. These properties are especiallybeneficial for pediatric, geriatric and neurodegenerative diseasepatients where proper and complete dosing can be difficult.

In specific embodiments, advantages of OTFs include the thin film'sability to dissolve rapidly without the need for water provides analternative to patients with swallowing disorders and to patientssuffering from nausea, such as those patients receiving chemotherapy.

In specific embodiments, advantages of OTFs include the thin film drugdelivery has the potential to allow the development of sensitive drugtargets that may otherwise not be possible in tablet or liquidformulations.

In specific embodiments, advantages of OTFs include the ability of asublingual film to deliver a convenient, quick-dissolving therapeuticdose contained within an abuse-deterrent film matrix that cannot becrushed or injected by patients, and rapidly absorbs under the tongue toensure compliance.

In specific embodiments, advantages of OTFs include the ability of thethin film to facilitate absorption (e.g., 3 to 10 times) greater than anoral tablet. This includes, e.g., sublingual administration under thetongue.

In specific embodiments, advantages of employing a Cannabis concentrateinto an OTF or topical adhesive patch include the ease and conveniencein using a non-solid (e.g., liquid, tar, oil, syrup, etc.) Cannabisconcentrate, which may otherwise be problematic in formulating, e.g.,capsules, pills and tablets. In further embodiments, additionaladvantages include the ease and convenience in using a Cannabisconcentrate without the need for subsequent purification.

Additional advantages include the ability to use the Cannabis extract(which may include a significant and/or appreciable amount of organicsolvent), without subsequent removal of the solvent, prior to use inmanufacturing the OTF or topical adhesive patch. In such embodiments,the presence of the solvent will not pose any significant issues orconcerns in producing the OTF or topical adhesive patch, and in somesituations may aid in maintaining the solubility of the desiredcompounds in the Cannabis concentrate, which is used directly in the OTFor topical adhesive patch.

DETAILED DESCRIPTION

Reference will now be made in detail to certain claims of the invention,examples of which are illustrated in the accompanying drawings. Whilethe invention will be described in conjunction with the enumeratedclaims, it will be understood that they are not intended to limit thoseclaims. On the contrary, the invention is intended to cover allalternatives, modifications, and equivalents, which can be includedwithin the scope of the invention as defined by the claims.

References in the specification to “one embodiment,” “an embodiment,”“an example embodiment,” and the like, indicate that the embodimentdescribed can include a particular feature, structure, orcharacteristic, but every embodiment may not necessarily include theparticular feature, structure, or characteristic. Moreover, such phrasesare not necessarily referring to the same embodiment. Further, when aparticular feature, structure, or characteristic is described inconnection with an embodiment, it is submitted that it is within theknowledge of one of ordinary skill in the art to affect such feature,structure, or characteristic in connection with other embodimentswhether or not explicitly described.

Values expressed in a range format should be interpreted in a flexiblemanner to include not only the numerical values explicitly recited asthe limits of the range, but also to include all the individualnumerical values or sub-ranges encompassed within that range as if eachnumerical value and sub-range is explicitly recited. For example, arange of “about 0.1% to about 5%” or “about 0.1% to 5%” should beinterpreted to include not just about 0.1% to about 5%, but also theindividual values (e.g., 1%, 2%, 3%, and 4%) and the sub-ranges (e.g.,0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range.

In this document, the terms “a,” “an,” or “the” are used to include oneor more than one unless the context clearly dictates otherwise. The term“or” is used to refer to a nonexclusive “or” unless otherwise indicated.In addition, it is to be understood that the phraseology or terminologyemployed herein, and not otherwise defined, is for the purpose ofdescription only and not of limitation. Any use of section headings isintended to aid reading of the document and is not to be interpreted aslimiting; information that is relevant to a section heading may occurwithin or outside of that particular section. Furthermore, allpublications, patents, and patent documents referred to in this documentare incorporated by reference herein in their entirety, as thoughindividually incorporated by reference. In the event of inconsistentusages between this document and those documents so incorporated byreference, the usage in the incorporated reference should be consideredsupplementary to that of this document; for irreconcilableinconsistencies, the usage in this document controls.

In the methods or processes described herein, the steps can be carriedout in any order without departing from the principles of the invention,except when a temporal or operational sequence is explicitly recited.

Furthermore, specified steps can be carried out concurrently unlessexplicit claim language recites that they be carried out separately. Forexample, a claimed step of doing X and a claimed step of doing Y can beconducted simultaneously within a single operation, and the resultingprocess will fall within the literal scope of the claimed process.

The term “about” as used herein can allow for a degree of variability ina value or range, for example, within 10%, within 5%, or within 1% of astated value or of a stated limit of a range. When a range or a list ofsequential values is given, unless otherwise specified any value withinthe range or any value between the given sequential values is alsodisclosed.

The term “substantially” as used herein refers to a majority of, ormostly, as in at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%,98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more.

As used herein, “Cannabis” refers to a genus of flowering plants thatincludes a single species, Cannabis sativa, which is sometimes dividedinto two additional species, Cannabis indica and Cannabis ruderalis.These three taxa are indigenous to Central Asia, and South Asia.Cannabis has long been used for fiber (hemp), for seed and seed oils,for medicinal purposes, and as a recreational drug. Various extractsincluding hashish and hash oil are also produced from the plant.Suitable strains of Cannabis include, e.g., Indica-dominant (e.g.,Blueberry, BC Bud, Holland's Hope, Kush, Northern Lights, Purple, andWhite Widow), Pure sativa (e.g., Acapulco Gold and Malawi Gold(Chamba)), and Sativa-dominant (e.g., Charlotte's Web, Diesel, Haze,Jack Herer, Shaman, Skunk, Sour, and Te Puke Thunder). The Cannabis caninclude any physical part of the plant material, including, e.g., theleaf, bud, flower, trichome, seed, or combination thereof. Likewise, theCannabis can include any substance physically derived from Cannabisplant material, such as, e.g., kief and hashish.

As used herein, “kief” refers to the resin glands (or trichomes) ofCannabis which may accumulate in containers or be sifted from loose dryCannabis flower with a mesh screen or sieve. Kief typically contains amuch higher concentration of psychoactive cannabinoids, such as THC,than that of the Cannabis flowers from which it is derived.Traditionally, kief has been pressed into cakes of hashish forconvenience in storage, but can be vaporized or smoked in either form.

As used herein, “hashish” refers to a Cannabis product composed ofcompressed or purified preparations of stalked resin glands, calledtrichomes. It contains the same active ingredients—such as THC and othercannabinoids—but in higher concentrations than unsifted buds or leaves.

As used herein, “leaf” refers to an organ of a vascular plant, asdefined in botanical terms, and in particular, in plant morphology. Inreference to Cannabis, the first pair of leaves usually have a singleleaflet, the number gradually increasing up to a maximum of aboutthirteen leaflets per leaf (usually seven or nine), depending on varietyand growing conditions. At the top of a flowering plant, this numberagain diminishes to a single leaflet per leaf. The lower leaf pairsusually occur in an opposite leaf arrangement and the upper leaf pairsin an alternate arrangement on the main stem of a mature plant.

As used herein, “bud” refers to a flower-bearing stem or branch of theCannabis plant, especially a stem or branch bearing a mass of femaleflowers with associated leaves. The stem or branch bearing the femaleflowers can be fresh, or can be dried. The pistils of the femaleCannabis flower are surrounded by a mass of trichome-rich petals andleaves, and can contain higher concentrations of cannabinoids than dothe plant leaves or stems. A bud, e.g., a mass of female flowers andassociated leaves, usually covered with trichomes, can be furtherprocessed mechanically, i.e., “trimming” or “cleaning” the stem bearingthe female flowers by removal of larger leaves and stem material. Buds,and cleaned buds, can be used as a Cannabis plant material in practiceof a method of the invention.

As used herein, “trichome” refers to a fine outgrowth or appendage onplants and certain protists. They are of diverse structure and function.Examples are hairs, glandular hairs, scales, and papillae. In referenceto Cannabis, the trichome is a glandular trichome that occurs mostabundantly on the floral calyxes and bracts of female plants.

As used herein, “seed” refers to an embryonic plant enclosed in aprotective outer covering called the seed coat, usually with some storedfood. It is a characteristic of spermatophytes (gymnosperm andangiosperm plants) and the product of the ripened ovule which occursafter fertilization and some growth within the mother plant. Theformation of the seed completes the process of reproduction in seedplants (started with the development of flowers and pollination), withthe embryo developed from the zygote and the seed coat from theinteguments of the ovule.

As used herein, “Cannabis sativa L.” or “Cannabis sativa” refers to anannual herbaceous plant in the Cannabis genus, a species of theCannabaceae family.

As used herein, “Cannabis indica Lam” or “Cannabis indica” refers to anannual plant in the Cannabaceae family. A putative species of the genusCannabis, it is typically distinguished from Cannabis sativa. Cannabissativa and Cannabis indica can interbreed, so the two strains can beviewed as sub-species or land races. Interbred stains comprising geneticmaterial from both sativa and indica strains can be termed“sativa-dominant” or “indica-dominant”, depending upon perceivedphysical and psychotropic properties of the hydbrids. The mixedinterbred strains can be themselves reproductively viable.

As used herein, “Cannabis ruderalis Janisch” or “Cannabis ruderalis”refers to a species of Cannabis originating in central Russia. Itflowers earlier than C. indica or C. sativa, does not grow as tall, andcan withstand much harsher climates than either of them. Cannabisruderalis will produce flowers based on its age, rather than light cycle(photoperiod) changes which govern flowering in C. sativa and C. indicavarieties. This kind of flowering is also known as “autoflowering.”

The Cannabis plant material contains suitable and desirable compounds,useful in the pharmaceutical dosage forms and methods of medicaltreatment described herein. The suitable and desirable compounds fallwithin one or more the following classes of compounds: cannabinoids,terpenoids, and flavonoids. These compounds can be obtained from theCannabis in a pure or partially pure state. The compounds obtained fromthe Cannabis can be in the form of an extract of Cannabis, or aconcentrate of Cannabis.

As used herein, “extract” refers to a substance obtained by extracting araw material, using a solvent system. The term “extract of Cannabis”refers to a substance obtained by extracting Cannabis (or any partthereof). In specific embodiments, the process of extracting a rawmaterial using a solvent includes a hot solvent extraction. Inalternative embodiments, the process of extracting a raw material usinga solvent includes supercritical fluid extraction (SFE), such as, e.g.,a fractional supercritical fluid extraction (FSFE). In reference toCannabis, suitable extracts include, e.g., hash oil, tincture, orcombination thereof.

In specific embodiments, the extract of Cannabis fulfils the definitionof “botanical drug substance” provided in the Guidance for IndustryBotanical Drug Products Draft Guidance, August 2000, US Department ofHealth and Human Services, Food and Drug Administration Center for DrugEvaluation and Research of: “A drug substance derived from one or moreplants, algae, or macroscopic fungi. It is prepared from botanical rawmaterials by one or more of the following processes: pulverization,decoction, expression, aqueous extraction, ethanolic extraction, orother similar processes.”

As used herein, “tincture” refers to a solvent extract of plant oranimal material, a solution of such, or of a low volatility substance.

As used herein, “hash oil” refers to a form of Cannabis. It is aresinous matrix of cannabinoids obtained from the Cannabis plant bysolvent extraction, formed into a hardened or viscous mass. Hash oil canbe the most potent of the main Cannabis products because of its high THCcontent which can vary depending on the plant.

As used herein, “concentrate” or “essential oil” refers to a substanceobtained by extracting a raw material, using a solvent, wherein thesolvent has substantially been removed. In specific embodiments, theprocess of extracting a raw material using a solvent includes a hotsolvent extraction. In alternative embodiments, the process ofextracting a raw material using a solvent includes supercritical fluidextraction (SFE), such as, e.g., a fractional supercritical fluidextraction (FSFE).

As such, the term “Cannabis concentrate” or “Cannabis essential oil”refers to a substance obtained by extracting Cannabis (or any partthereof), wherein the solvent has substantially been removed. TheCannabis concentrate can be enriched with the desired product (e.g.cannabinoids, terpenoids, and/or flavonoids) from the Cannabis plantmaterial. Additionally, compared to the Cannabis plant material, theCannabis concentrate can contain a lower concentration of unwantedmaterial (e.g. terpenes, alkaloids, hemp oil, and/or cannabinoid acids).

As used herein, “cannabinoid” refers to a class of diverse chemicalcompounds that act on cannabinoid receptors on cells that repressneurotransmitter release in the brain. These receptor proteins includethe endocannabinoids (produced naturally in the body by humans andanimals), the phytocannabinoids (found in Cannabis and some otherplants), and synthetic cannabinoids (manufactured chemically). The mostnotable cannabinoid is the phytocannabinoid Δ9-tetrahydrocannabinol(THC), the primary psychoactive compound of Cannabis. Cannabidiol (CBD)is another major constituent of the plant, representing up to 40% inextracts of the plant resin. There are at least 85 differentcannabinoids isolated from Cannabis, exhibiting varied effects.

As used herein, “terpenoid” or “isoprenoid” refers to a large anddiverse class of naturally occurring organic chemicals similar toterpenes, derived from five-carbon isoprene units assembled and modifiedin thousands of ways. Most are multicyclic structures that differ fromone another not only in functional groups but also in their basic carbonskeletons. These lipids can be found in all classes of living things,and are the largest group of natural products. Plant terpenoids are usedextensively for their aromatic qualities. They play a role intraditional herbal remedies and are under investigation forantibacterial, antineoplastic, and other pharmaceutical functions.Terpenoids contribute to the scent of eucalyptus, the flavors ofcinnamon, cloves, and ginger, the yellow color in sunflowers, and thered color in tomatoes. Well-known terpenoids include citral, menthol,camphor, salvinorin A in the plant Salvia divinorum, the cannabinoidsfound in Cannabis, ginkgolide and bilobalide found in Ginkgo biloba, andthe curcuminoids found in turmeric and mustard seed.

As used herein, “flavonoid” refers to a class of plant secondarymetabolites. Flavonoids were referred to as Vitamin P (probably becauseof the effect they had on the permeability of vascular capillaries) fromthe mid-1930s to early 50s, but the term has since fallen out of use.According to the IUPAC nomenclature, they can be classified into:flavonoids or bioflavonoids; isoflavonoids, derived from3-phenylchromen-4-one (3-phenyl-1,4-benzopyrone) structure; andneoflavonoids, derived from 4-phenylcoumarine (4-phenyl-1,2-benzopyrone)structure.

As used herein, “supercritical fluid extraction” or “SFE” refers to theprocess of separating one or more components (extractant) from another(matrix) using supercritical fluids as the extracting solvent.Extraction is usually from a solid matrix (e.g., Cannabis plantmaterial), but can also be from liquids or resinous material (e.g., hashoil). SFE can be used as a sample preparation step for analyticalpurposes, or on a larger scale to either strip unwanted material from aproduct (e.g. terpenes, alkaloids, hemp oil, and/or cannabinoid acidsfrom Cannabis plant material) and/or collect a desired product (e.g.cannabinoids, terpenoids, and/or flavonoids). Although numeroussupercritical fluids can be used, carbon dioxide (CO₂) is the most usedsupercritical fluid, sometimes modified by co-solvents such as ethanolor methanol. Extraction conditions for supercritical fluids are abovethe critical temperature of (e.g., 31° C. for carbon dioxide) andcritical pressure of (e.g., 74 bar for carbon dioxide). Addition ofmodifiers may slightly alter this.

The properties of a supercritical fluid can be altered by varying thepressure and temperature, allowing selective extraction. For example,various substances can be extracted from a plant with low pressures(e.g., 100 bar), whereas extraction from the same plant (and samesolvent system) with high pressure (e.g., 750 bar) provides differentsubstances. Likewise, changing the extraction temperature (from onesupercritical fluid extraction to another) can yield differentsubstances. Moreover, various substances can be extracted from a plantwith a solvent system having a specified combination of polarity (e.g.,non-polar) and proticity (e.g., protic), whereas extraction from thesame plant at the same temperature and pressure can provide differentsubstances upon extraction from the plant with a solvent system having adifferent combination of polarity (e.g., non-polar) and proticity (e.g.,aprotic). As such, various embodiments of the present invention providefor a supercritical fluid extraction carried out multiple times (i.e., afractional supercritical fluid extraction), altering the pressure,temperature, polarity of the solvent system, and/or proticity of thesolvent system. In doing so, unwanted material (e.g. terpenes,alkaloids, hemp oil, and/or cannabinoid acids) can be separated fromCannabis plant material, while obtaining the desired product (e.g.cannabinoids, terpenoids, and/or flavonoids).

Extraction is a diffusion-based process, with the solvent required todiffuse into the matrix, and the extracted material to diffuse out ofthe matrix into the solvent. Diffusivities are much faster insupercritical fluids than in liquids, and therefore extraction can occurfaster. Also, there is no surface tension and viscosities are much lowerthan in liquids, so the solvent can penetrate into small pores withinthe matrix inaccessible to liquids. Both the higher diffusivity andlower viscosity significantly increase the speed of the extraction: Anextraction using an organic liquid may take several hours, whereassupercritical fluid extraction can typically be completed in 10 to 60minutes.

As used herein, “solvent system” refers to one or more solvents thatdissolves a solute (a chemically different liquid, solid or gas),resulting in a solution. The maximum quantity of solute that candissolve in a specific volume of solvent system varies with temperatureand pressure. The solvent system can have a specified polarity andproticity. As such, solvent system can be polar, nonpolar, protic, oraprotic, wherein each of these terms is used in a relative manner.

As used herein, “polarity” refers to a separation of electric chargeleading to a molecule or its chemical groups having an electric dipoleor multipole moment. Polar molecules interact through dipole—dipoleintermolecular forces and hydrogen bonds. Molecular polarity isdependent on the difference in electronegativity between atoms in acompound and the asymmetry of the compound's structure. Polarityunderlies a number of physical properties including surface tension,solubility, and melting- and boiling-points.

As used herein, “polar” or “polar solvent” refers to a molecule having anet dipole as a result of the opposing charges (i.e., having partialpositive and partial negative charges) from polar bonds arrangedasymmetrically. Water (H₂O) is an example of a polar molecule since ithas a slight positive charge on one side and a slight negative charge onthe other. The dipoles do not cancel out resulting in a net dipole. Dueto the polar nature of the water molecule itself, polar molecules aregenerally able to dissolve in water. Another example includes sugars(like sucrose), which have many polar oxygen—hydrogen (—OH) groups andare overall highly polar.

As used herein, “nonpolar” or “nonpolar solvent” refers to a moleculehaving an equal sharing of electrons between the two atoms of a diatomicmolecule or because of the symmetrical arrangement of polar bonds in amore complex molecule. For example, the boron trifluoride molecule (BF₃)has a trigonal planar arrangement of three polar bonds at 120°. Thisresults in no overall dipole in the molecule. In methane, the bonds arearranged symmetrically (in a tetrahedral arrangement) so there is nooverall dipole. In the methane molecule (CH₄) the four C—H bonds arearranged tetrahedrally around the carbon atom. Each bond has polarity(though not very strong). However, the bonds are arranged symmetricallyso there is no overall dipole in the molecule. The diatomic oxygenmolecule (O₂) does not have polarity in the covalent bond because ofequal electronegativity, hence there is no polarity in the molecule

Examples of nonpolar solvents include, e.g., carbon dioxide (CO₂),hydrogen (H₂), neon (Ne), nitrogen (N₂), argon (Ar), methane (CH₄),ethane (CH₃CH₃), and propane (CH₃CH₂CH₃).

Organic solvents can range from nonpolar to polar, depending upon themolecular composition. For instance, organic solvents can be classifiedin a series ranging from nonpolar to polar, such as aliphatichydrocarbon, aromatic hydrocarbon, halocarbon, ether, ketone, alcohol.By selection of an organic solvent, e.g. as a solvent or a cosolvent(with CO₂, etc.) in a supercritical fluid extraction, a selection of thepolarity class of the substances extracted can be exerted. By using lesspolar solvent or cosolvent, a less polar set of, e.g., cannabinoidconstituents can be obtained as a purified fraction. By use of a morepolar solvent or cosolvent, a set of cannabinoid constituents of greaterpolarity can be selectively obtained as a purified fraction.

As used herein, “proticity” refers to the degree (or number) ofoccurrences of a hydrogen atom bound to an oxygen atom (as in a hydroxylgroup), and/or a hydrogen atom bound to a nitrogen atom (as in an aminegroup), relative to the size or molecular weight of the molecule.

As used herein, “protic” or “protic solvent” refers to any solvent thatcontains labile H+. The molecules of such solvents readily donateprotons (H+) to reagents.

As used herein, “aprotic” or “aprotic solvent” refers to any solventthat does not contain labile H+. The molecules of such solvents cannotreadily donate protons (H+) to reagents.

As used herein, “mutually exclusive” refers to variables being relatedsuch that each excludes or precludes the other. For example, in themethods described herein to obtain a Cannabis extract, fractionalsupercritical fluid extract (FSFE) can be employed. In variousembodiments of such FSFE, the SFE can be carried out two times (FSFE 1and FSFE 2), each with the same solvent system and each at a differenttemperature and pressure. In such embodiments, while the solvent systemof FSFE 1 and FSFE 2 are the same, the temperatures and pressures (ofFSFE 1 and FSFE 2) are mutually exclusive. Specifically, each of thetemperature and pressure of FSFE 1 is mutually exclusive of (e.g.,different from) the temperature and pressure of FSFE 2.

As used herein, “fresh” refers to a plant (or any physical part thereof,such as a leaf, flowering bud, seed, etc.) that has been harvestedwithin the past 21 days. In specific embodiments, the harvesting wouldhave occurred within the past 14 days, within the past 10 days, withinthe past 7 days, or within the past 3 days.

As used herein, “dried” refers to a plant (or any physical part thereof,such as a leaf, bulb, seed, etc.) has undergone a drying process, suchthat an appreciable and significant amount of water (or moisture) hasbeen removed. The drying process can include, e.g., an elevatedtemperature, a decreased pressure, or a combination thereof.

As used herein, “moisture content” or “water content” refers to thequantity of water contained in a material, such as, e.g., Cannabis plantmaterial, or any part thereof. For example, dried Cannabis can have amoisture content of less than about 10 wt. %, less than about 5 wt. %,or less than about 1 wt. %.

As used herein, “harvested” refers to the act of gathering a crop (e.g.,Cannabis) or any physical part thereof.

As used herein, “partially purified” refers to a raw material (e.g.,Cannabis) that has undergone one or more processes (e.g., supercriticalfluid extraction), such that the resulting product (e.g., extract ofCannabis) contains a desired substance (e.g., THC) in a concentrationhigher than the raw material. As such, the partially purified substance(e.g., extract of Cannabis) is said to be enriched with a desiredsubstance (e.g., THC), relative to the raw material (e.g., Cannabis). Asused herein, “partially purifying” refers to a process that provides apartially purified product. For example, the partially purifiedsubstance can be up to about 85% pure, up to about 75% pure, or up toabout 50% pure.

“Purified fractions” can contain components present in differentrelative amounts or concentrations than found in the Cannabis plantmaterial that has undergone a process of the invention. By this means,purified fractions of the total plant extract can be said to be“enriched” or “depleted” in specific components relative to otherspecific components. For instance, a purified fraction of plant materialcan contain a higher proportion of, e.g., cannabidiol relative totetrahydrocannabinol, than is present in the plant material undergoingextraction. Purified fractions can be advantageous when it is desired toadminister to a patient an extract that has a lower level of anundesired component (e.g., THC) and a higher level of a desiredtherapeutic constituent (e.g., cannabidiol).

As used herein, “purifying” refers to a process of rendering asubstance, or a set of substances, pure, i.e. substantially free of, orhaving a lower relative content of, undesirable components. For example,the purified substance can be at least about 90% pure, at least about95% pure, or at least about 98% pure.

As used herein, “terpene” refers to a hydrocarbon or derivative thereof,found as a natural product and biosynthesized by oligomerization ofisoprene units. A terpene can be acyclic, monocyclic, bicyclic, ormulticyclic. Examples include limonene, pulegone, caryophyllene epoxide,and the like.

As used herein, “alkaloid” refers to a natural product containing atleast one basic nitrogen atom capable of forming salts with acids.

As used herein, “hemp oil” refers to a triglyceride, i.e., a triester ofglycerol with fatty acids, typically extracted from hemp seeds withnon-polar solvent.

As used herein, “cannabinoid acid” refers to a compound found naturallyin a Cannabis species, formed by condensation of an alkyl-resorcinol anda terpene, which comprises a carboxylic acid group. Examples includecannabidiolic acid, tetrahydrocannabinolic acid, cannabichromenic acid,cannabigerolic acid, and the like.

As used herein, “multiple” refers to more than one, e.g., 2, 3, 4, 5,etc.

As used herein, “independently” refers to variables that are notinfluenced or controlled by other variables. Specifically, selection ofone variable will not influence or control the selection of othervariables. For example, in the methods described herein to obtain aCannabis extract, fractional supercritical fluid extract (FSFE) can beemployed. In various embodiments of such FSFE, the SFE can be carriedout two times (FSFE 1 and FSFE 2), each with a different solvent system.In such embodiments, each of FSFE 1 and FSFE 2 can have the same ordifferent temperature. Likewise, in such embodiments, each of FSFE 1 andFSFE 2 can have the same or different pressure. In such embodiments,while the solvent system of FSFE 1 and FSFE 2 are different, thetemperatures and pressures (of FSFE 1 and FSFE 2) can be independentlyselected. In doing so, each of the temperature and pressure (of FSFE 1and FSFE 2) can be the same, or can be different.

As used herein, “combining” refers to the act of bringing into contacttwo or more substances. For example, in the methods described herein, aplant material (e.g., Cannabis) can be combined with a solvent system.In doing so, the plant material and solvent system will be in closeproximity, such that they contact each other. The solvent system can beadded to a vessel containing the plant material or the plant materialcan be added to the vessel containing the solvent system.

As used herein, “discarding” refers to the act of casting aside,disposing of, or otherwise not using in a subsequent process, step, orarticle of manufacture.

As used herein, “chromatography” refers to a process for separation ofconstituents of a mixture of organic compounds wherein the compounds aredifferentially absorbed and eluted from a solid phase by a liquidsolvent (liquid chromatography) or by a gas (gas chromatograph).Representative chromatography include, e.g., high pressure liquidchromatography (HPLC).

As used herein, “adsorption” refers to a physical process whereby amolecule enters into an energetically favorable association with a solidsurface.

As used herein, “crystallization” refers to a process whereby a sampleof a molecular entity forms crystals, usually on precipitation from asolvent or solvent mixture.

As used herein, “distillation” refers to a purification process wherebyliquid components are separated on the basis of boiling point, oftenunder reduced atmospheric pressure, in a still.

As used herein, “liquid-liquid extraction” refers to a process wherebychemical compounds are partitioned between two substantially immiscibleliquid phases.

As used herein, “filtration” refers to a process whereby a solid and aliquid are separated by passage of a mixture of the two through a filtermedium, where the solid material is retained and the liquid passesthrough.

As used herein, “fractional distillation” refers to a distillation asdescribed above, where multiple components are separated sequentially byincreasing boiling point, often under reduced atmospheric pressure.

As used herein, “precipitation” refers to a separation from a solutionof a solid material.

As used herein, “recrystallization” refers to a purification processwhereby a crystalline material is dissolved, then subsequently again putunder conditions where crystallization occurs, usually in a highlycontrolled manner such that a substantial increase in purity of thecompound is obtained.

As used herein, “sublimation” refers to a physical process whereby asolid material passes into a vapor phase without passing through anintervening liquid phase.

In specific embodiments, the desired extract (or concentrate) ofCannabis, relative to the starting plant material, will be enriched withthe desired product (e.g. cannabinoids, terpenoids, and/or flavonoids).In further embodiments, the desired extract (or concentrate) ofCannabis, relative to the undesired extract of Cannabis, will beenriched with the desired product (e.g. cannabinoids, terpenoids, and/orflavonoids). In yet further embodiments, the undesired extract (orconcentrate) of Cannabis, relative to the desired extract of Cannabis,will be enriched with the undesired product (e.g. terpenes, alkaloids,hemp oil, and/or cannabinoid acids). As such, the FSFE can be employedto selectively obtain one or more desired substances from the Cannabisplant material, while selectively excluding one or more undesiredsubstances.

In specific embodiments, the desired extract (or concentrate) ofCannabis, relative to the starting plant material, will include a lowerconcentration of the undesired product (e.g. terpenes, alkaloids, hempoil, and/or cannabinoid acids). In further embodiments, the desiredextract (or concentrate) of Cannabis, relative to the undesired extractof Cannabis, will include a lower concentration of the undesired product(e.g. terpenes, alkaloids, hemp oil, and/or cannabinoid acids). In yetfurther embodiments, the undesired extract (or concentrate) of Cannabis,relative to the desired extract of Cannabis, will include a lowerconcentration of the desired product (e.g. cannabinoids, terpenoids,and/or flavonoids). As such, the FSFE can be employed to selectivelyobtain one or more desired substances from the Cannabis plant material,while selectively excluding one or more undesired substances.

As used herein, “enrich” refers to an increase the concentration oramount of one substance, relative to the concentration or amount ofanother substance; or one material containing a higher concentration oramount of a substance, compared to a second material's concentration oramount of that substance. The difference in the amount (weight/mass) canbe at least about 1%, at least about 5%, at least about 10%, at leastabout 25%, or at least about 50%. Likewise, the difference inconcentration can be at least about 1%, at least about 5%, at leastabout 10%, at least about 25%, or at least about 50%. In reference to“higher concentration” and “lower concentration,” the difference inconcentration can be at least about 1%, at least about 5%, at leastabout 10%, at least about 25%, or at least about 50%.

As used herein, “relative concentration” refers to the concentration ofa specified substance (or a combination of specified substances) that ispresent in a lower concentration (“lower relative concentration”), or ispresent in a higher concentration (“higher relative concentration”),compared to the concentration of the same substances in the Cannabisplant material. In specific embodiments, the Cannabis concentrate(compared to the Cannabis plant material) can include a higher relativeconcentration of compound “X,” or a lower relative concentration ofcompound “Z.” In such an embodiment, the concentration of compound “X”will be higher in the Cannabis concentrate compared to the concentrationof compound “X” in the Cannabis plant material. Likewise, theconcentration of compound “Z” will be lower in the Cannabis concentratecompared to the concentration of compound “Z” in the Cannabis plantmaterial. The increase (or decrease) can range anywhere from about 10%to 100,000 fold. In specific embodiments, the increase (or decrease) canbe about 10% to 10,000 fold; about 20% to 1,000 fold; about 50% to 100fold; about 2 fold to 100 fold; about 3 fold to 50 fold; or about 5 foldto 25 fold.

As used herein, “pharmaceutical dosage form” refers to a pharmaceuticalproduct in the form in which it is marketed for use, typically involvinga mixture of active drug components and nondrug components (excipients),along with other non-reusable material that may not be considered eitheringredient or packaging (such as a capsule shell, for example). The termpharmaceutical dosage form can also refer only to the chemicalformulation of a drug product's constituent drug substance(s) and anyblends involved, without considering matters beyond that (like how it'sultimately configured as a consumable product such as a capsule, patch,etc.).

Depending on the method/route of administration, pharmaceutical dosageforms come in several types. These include many kinds of liquid, solid,and semisolid dosage forms. Common pharmaceutical dosage forms includepill, tablet, or capsule, drink or syrup, and natural or herbal formsuch as plant or food of sorts, among many others. Notably, the route ofadministration (ROA) for drug delivery is dependent on the dosage formof the substance in question. A liquid pharmaceutical dosage form is theliquid form of a dose of a chemical compound used as a drug ormedication intended for administration or consumption.

Various pharmaceutical dosage forms may exist for a single particulardrug, since different medical conditions can warrant different routes ofadministration. For example, persistent nausea and emesis or vomitingmay make it difficult to use an oral dosage form, and in such a case, itmay be necessary to utilize an alternate route such as inhalational,buccal, sublingual, nasal, suppository or parenteral instead.Additionally, a specific pharmaceutical dosage form may be a requirementfor certain kinds of drugs, as there may be issues with various factorslike chemical stability or pharmacokinetics.

Exemplary pharmaceutical dosage forms include, e.g., pills, osmoticdelivery systems, elixirs, emulsions, hydrogels, suspensions, syrups,capsules, tablets, orally dissolving tablets (ODTs), gel capsules, thinfilms, adhesive topical patches, lollipops, lozenges, chewing gum, drypowder inhalers (DPIs), vaporizers, nebulizers, metered dose inhalers(MDIs), ointments, transdermal patches, intradermal implants,subcutaneous implants, and transdermal implants.

As used herein, “oral delivery” or “oral administration” refers to aroute of administration wherein the pharmaceutical dosage form is takenthrough the mouth. Oral administration is a part of enteraladministration, which also includes buccal (dissolved inside the cheek),sublabial (dissolved under the lip) and sublingual administration(dissolved under the tongue). Enteral medications come in various forms,including: tablets to swallow, chew or dissolve in water or under thetongue; capsules and chewable capsules (with a coating that dissolves inthe stomach or bowel to release the medication there); time-release orsustained-release tablets and capsules (which release the medicationgradually); powders or granules; teas; drops; and liquid medications orsyrups.

As used herein, “ophthalmic delivery” or “ophthalmic administration”refers to a route of administration wherein the pharmaceutical dosageform is taken to, or through, the eye.

As used herein, “nasal delivery” or “nasal administration” refers to aroute of administration wherein the pharmaceutical dosage form is takento, or through, the nose (e.g., nasal cavity).

As used herein, “dermal delivery” or “dermal administration” refers to aroute of administration wherein the pharmaceutical dosage form is takento, or through, the dermis (i.e., layer of skin between the epidermis(with which it makes up the cutis) and subcutaneous tissues).

As used herein, “pill” refers to a small, round, solid pharmaceuticaloral dosage form of medication that was in use before the advent oftablets and capsules. Pills were historically made by mixing the activeingredients with an excipient such as glucose syrup in a mortar andpestle to form a paste, then rolling the mass into a long cylindricalshape (called a “pipe”), and dividing it into equal portions, which werethen rolled into balls, and often coated with sugar to make them morepalatable. Today, pills include tablets, capsules, and variants thereoflike caplets—essentially anything with medication that can be digested,minus the liquid forms, falls into the pill category.

As used herein, “osmotic delivery system” or “osmotic controlled releaseoral delivery system” or “OROS” refers to a controlled release oral drugdelivery system in the form of a tablet. The tablet has a rigidwater-permeable jacket with one or more laser drilled small holes. Asthe tablet passes through the body, the osmotic pressure of waterentering the tablet pushes the active drug through the opening in thetablet.

As used herein, “capsule” refers to a solid pharmaceutical oral dosageform wherein the active (and inactive) ingredient is encapsulated.Encapsulation refers to a range of techniques used to enclose medicinesin a relatively stable shell known as a capsule, allowing them to, forexample, be taken orally or be used as suppositories. The two main typesof capsules include hard-shelled capsules, which are typically madeusing gelatin and contain dry, powdered ingredients or miniature pelletsmade by, e.g. processes of extrusion or spheronisation. These are madein two halves: a lower-diameter “body” that is filled and then sealedusing a higher-diameter “cape”. The second main type of capsules includesoft-shelled capsules, primarily used for oils and for activeingredients that are dissolved or suspended in oil. Both of theseclasses of capsules are made from aqueous solutions of gelling agentslike such as animal protein mainly gelatin; and plant polysaccharides ortheir derivatives like carrageenans and modified forms of starch andcellulose. Other ingredients can be added to the gelling agent solutionlike plasticizers such as glycerin and/or sorbitol to decrease thecapsule's hardness, coloring agents, preservatives, disintegrants,lubricants and surface treatment.

As used herein, “tablet” refers to a pharmaceutical dosage form thatincludes a mixture of active substances and excipients, usually inpowder form, pressed or compacted from a powder into a solid dose. Theexcipients can include diluents, binders or granulating agents, glidants(flow aids) and lubricants to ensure efficient tabletting; disintegrantsto promote tablet break-up in the digestive tract; sweeteners orflavours to enhance taste; and pigments to make the tablets visuallyattractive. A polymer coating is often applied to make the tabletsmoother and easier to swallow, to control the release rate of theactive ingredient, to make it more resistant to the environment(extending its shelf life), or to enhance the tablet's appearance.

As used herein, “orally dissolving tablet” or “ODT” refers topharmaceutical dosage form designed to be dissolved on the tongue ratherthan swallowed whole. The ODT serves as an alternative dosage form forpatients who experience dysphagia (difficulty in swallowing) or forwhere compliance is a known issue and therefore an easier dosage form totake ensures that medication is taken. Common among all age groups,dysphagia is observed in about 35% of the general population, as well asup to 60% of the elderly institutionalized population and 18-22% of allpatients in long-term care facilities. Additional reasons to use ODTsinclude the convenience of a tablet that can be taken without water aswell as the inability of the patient to eat or drink (e.g., nauseaand/or vomiting).

As used herein, “oral thin film,” “OTF,” “oral dissolving film,” “oraldrug strip,” “oral thin film,” “thin film,” “orally dissolvable filmstrip,” or “oral strip” refers to a product used to administer activeingredients via absorption in the mouth (buccally or sublingually), thestomach (gastrically), and/or via the small intestines (enterically).The OTF is edible and pharmaceutically acceptable. A film is preparedtypically using hydrophilic polymers that rapidly dissolves on thetongue, palatine tissue, or buccal cavity, delivering the activeingredient to the systemic circulation via dissolution when contact withliquid is made. The OTF (or more appropriately “thin film” or “TF”) canalso be used to adhere to mucosal tissue (e.g., at least one of mouth,nose, eye, vagina, and rectum), thereby locally delivering the activeingredient(s). As such, it is appreciated that those of skill in the artunderstand that reference to a thin film for use with mucosal tissue,such as nose, eye, vagina, and rectum, as an “oral thin film” or OTF isappropriate and acceptable.

The term “film” includes thin films and sheets, in any shape, includingrectangular, square, or other desired shape. The films described hereinmay be any desired thickness and size such that it may be placed intothe oral cavity of the user. For example, the films may have arelatively thin thickness of from about 0.1 to about 10 mils, or theymay have a somewhat thicker thickness of from about 10 to about 30 mils.For some films, the thickness may be even larger, i.e., greater thanabout 30 mils. In addition, the term “film” includes single-layercompositions as well as multi-layer compositions, such as laminatedfilms. The composition in its dried film form can effectively maintain arelatively uniform distribution of components through the application ofcontrolled drying of the film. For example, the film can have no morethan a 20%, 10%, 5%, or 1% variance of the active ingredient, per unitarea of the film.

As used herein, “adhesive topical patch” or “transdermal patch” refersto a medicated adhesive patch that is placed on the skin to deliver aspecific dose of medication through the skin and into the bloodstream. Atransdermal patch or transdermal system (TDS) is a medicated adhesivepatch that is placed on the skin to deliver a specific dose of drugthrough the skin and into the bloodstream. An advantage of a transdermaldrug delivery route over other types of medication delivery such asoral, topical, intravenous, intramuscular, etc. is that the patchprovides a controlled release of the medication into the patient,usually through either a porous membrane covering a reservoir ofmedication or through body heat melting thin layers of medicationembedded in the adhesive. The main disadvantage to transdermal deliverysystems stems from the fact that the skin is a very effective barrier;as a result, only medications whose molecules are small enough topenetrate the skin can effectively be delivered by this method.

The transdermal patch serves as an alternative dosage form for patientswho experience dysphagia (difficulty in swallowing). Additional reasonsto use transdermal patches include the convenience of a dosage form thatcan be taken without water as well as the inability of the patient toeat or drink (e.g., nausea and/or vomiting).

As used herein, “therapeutically effective amount” is intended toinclude an amount of a substance (or compound) described herein, or anamount of the combination of substances (or compounds) described herein,e.g., to treat or prevent the disease or disorder, or to treat thesymptoms of the disease or disorder, in a host. The combination ofsubstances (or compounds) is preferably a synergistic combination.Synergy, as described for example by Chou and Talalay, Adv. EnzymeRegul., 22:27 (1984), occurs when the effect of the compounds whenadministered in combination is greater than the additive effect of thecompounds when administered alone as a single agent. In general, asynergistic effect is most clearly demonstrated at suboptimalconcentrations of the compounds. Synergy can be in terms of lowercytotoxicity, increased activity, or some other beneficial effect of thecombination compared with the individual components.

As used herein, “treating” or “treat” includes: (i) preventing apathologic condition from occurring (e.g. prophylaxis); (ii) inhibitingthe pathologic condition or arresting its development; (iii) relievingthe pathologic condition; and/or (iv) diminishing symptoms associatedwith the pathologic condition.

The phrase “pharmaceutically acceptable” refers to those compounds,materials, compositions, and/or dosage forms that are, within the scopeof sound medical judgment, suitable for use in contact with the tissuesof human beings and animals without excessive toxicity, irritation,allergic response, or other problems or complications commensurate witha reasonable benefit/risk ratio.

As used herein, “neuro inflammation” refers to a medical conditionwherein neural tissue undergoes an inflammatory response.

As used herein, “epilepsy” refers to a medical condition characterizedby petit mal or grand mal seizures, resulting from aberrant brainelectrical activity.

As used herein, “Alzheimer's disease” refers to a form of dementia inpatients characterized by memory loss and formation of amyloid plaquesin brain tissue.

As used herein, “oxidative injury” refers to an injury sustained bytissue components due to the reaction of those components with oxidizingsubstances.

As used herein, “vomiting” refers to a symptom of a medical conditionwhereby the contents of the stomach are ejected through the mouth.

As used herein, “nausea” refers to a sensation experienced by a patientof an imminent need to vomit, accompanied by dizziness ordisorientation.

As used herein, “anxiety” refers to an emotional state in which a personexperiences fear of some real or imagined future event.

As used herein, “anorexia” refers to a symptom characterized by loss ofappetite for food.

As used herein, “arthritis” refers to inflammation of the bone fasciaproducing pain and immobility.

As used herein, “schizophrenia” refers to a mental health statecharacterized by disorientation, delusion, disorganized thinking, lackof emotion, and mental imbalance.

As used herein, “multiple sclerosis” refers to an inflammatory diseasewherein myelin-producing cells surrounding neurons undergodeterioration, resulting in physical and mental symptoms.

As used herein, “joint inflammation” refers to an inflammatory responseoccurring in the bone joints, producing pain and immobility.

As used herein, “joint pain” refers to pain associated with the relativemotion of two or more bones at a mutual joint thereof.

As used herein, “symptoms associated with AIDS” refers to those symptomsproduced by infection of a patient with Human Immunodeficiency Virus(HIV), including reduced resistance to infections and formation ofopportunistic tumors.

As used herein, “chronic pain” refers to pain experienced over aprolonged period of time.

As used herein, “acute pain” refers to pain of a high degree ofseverity.

As used herein, “neuropathic pain and spasticity” refers to pain andloss of muscle control produced by damage or disease that affects thesomatosensory system, which can results from injury or disease of thecentral or peripheral nervous systems.

As used herein, “inflammatory bowel diseases (IBD)” refers toinflammatory conditions afflicting the colon and small intestine,including Crohn's disease and ulcerative colitis.

As used herein, “tumor neovascularization” refers to the induction ofblood vessel growth by a tumor, supplying increased blood flow to theneoplasm.

As used herein, “tumor growth” refers to the abnormal growth ofneoplasms with the body.

As used herein, “cancer cell migration” refers to the physicaltranslocation of metastatically transformed neoplastic cells within thebody.

As used herein, “cancer cell adhesion” refers to the adhesion ofmetastatically transformed neoplastic cells to tissues and structureswithin the body.

As used herein, “cancer cell invasion” refers to a process wherebymetastatically transformed neoplastic cells invade other tissues of thebody.

As used herein, “cancer cell metastasization” refers to a cellularprocess whereby a cell becomes cancerous and capable of inducingmetastatic transformation in normal cells, thereby spreading a cancer.

As sued herein “time release technology” refers to a mechanism used inpharmaceutical dosage forms (e.g., pill, tablet, capsule, transdermalpatch, etc.) to dissolve a drug over time in order to be released slowerand steadier into the bloodstream, while having the advantage of beingtaken at less frequent intervals than immediate-release (IR)formulations of the same drug. The time release technology can includesustained-release (SR), sustained-action (SA), extended-release (ER, XR,XL), timed-release (TR), controlled-release (CR), modified release (MR),or continuous-release (Contin).

There are certain considerations for the formation of time releaseformulation: (i) if the active compound has a long half-life (over 6hours), it is sustained on its own; (ii) if the pharmacological activityof the active compound is not related to its blood levels, timereleasing has little or no purpose; (iii) if the absorption of theactive compound involves an active transport, the development of atime-release product may be problematic; and (iv) if the active compoundhas a short half-life, it would require a large amount to maintain aprolonged effective dose. In this case, a broad therapeutic window isnecessary to avoid toxicity; otherwise, the risk is unwarranted andanother mode of administration would be recommended.

As used herein, “single daily dosage” refers to a dose suitable for asingle administration over a 24 hour period. The dose is configured fora single administration over a 24 hour period.

Supercritical Fluid Extraction (SFE)

Supercritical fluid extraction is an extraction wherein a fluid at atemperature and pressure above its critical point is employed; or afluid above its critical temperature, regardless of pressure, isemployed. Below the critical point, the fluid can coexist in both gasand liquid phases, but above the critical point there is only one phase.Equipment and techniques for carrying out supercritical fluid extractionare known to those skilled in the art. See, McHugh, M. And Krukonis, V.,Supercritical Fluid Extraction, 2nd ed, Butterworth-Heinemann, Boston,1994; Johnston, K. P., Penninger, J. M. L., Supercritical Fluid Scienceand Technology, ACS Symposium Series 406, American Chemical Society,Washington, D.C.; and Taylor, L. T., Supercritical Fluid Extraction,John Wiley & Sons, New York, 1996.

In a supercritical fluid extraction, thermodynamic and transportproperties of supercritical fluid are a function of density, whichdepends strongly on the fluid's pressure and temperature. The densitymay be adjusted from a gas-like value of 0.1 g/ml to a liquid-like valueas high as 1.2 g/ml. Furthermore, as conditions approach the criticalpoint, the effect of temperature and pressure on density becomes muchmore significant. For example, increasing the density of supercriticalcarbon dioxide from 0.2 to 0.5 g/ml typically requires raising thepressure from 85 atm to 140 atm (8.6 megapascals to 14.2 megapascals) at158° F. (70° C.), but at 95° F. (35° C.) the required change is onlyfrom 65 atm to 80 atm (6.61 Mpa to 8.1 Mpa).

In specific embodiments, the supercritical fluid extraction can becarried out multiple times. In such embodiments, the supercritical fluidextraction is a fractional supercritical fluid extraction. “Fractionalsupercritical fluid extraction” (hereinafter “FSFE”) refers to asupercritical fluid extraction that is carried out multiple times. Eachtime the supercritical fluid extraction is carried out, at least one ofthe (i) solvent system (with respect to polarity and proticity), (ii)temperature and (iii) pressure will vary.

For example, in reference to Cannabis, the FSFE can include asupercritical fluid extraction that is carried out two times, threetimes, four times, etc. At each time (occurrence), the temperature,pressure, period of time, and supercritical fluid solvent system areeach independently selected (e.g., can independently be the same ordifferent).

When the SFE is carried out two times, the FSFE can include: (a)contacting Cannabis plant material with a supercritical fluid solventsystem at a suitable pressure (e.g., between about 750 psi and 25,000psi), and at a suitable temperature (e.g., between about −15° C. and200° C.), to provide an extract of Cannabis and an extracted Cannabisplant material; (b) removing the supercritical fluid solvent system fromthe extract of Cannabis; (c) contacting the extracted Cannabis with asecond supercritical fluid solvent system at a suitable pressure (e.g.,between about 750 psi and 25,000 psi), and at a suitable temperature(e.g., between about −15° C. and 200° C.), to provide a second extractof Cannabis and a second extracted Cannabis plant material; and (d)removing the second supercritical fluid solvent system from the secondextract of Cannabis.

When the SFE is carried out three times, the FSFE can include: (a)contacting Cannabis plant material with a supercritical fluid solventsystem at a suitable pressure (e.g., between about 750 psi and 25,000psi), and at a suitable temperature (e.g., between about −15° C. and200° C.), to provide an extract of Cannabis and an extracted Cannabisplant material; (b) removing the supercritical fluid solvent system fromthe extract of Cannabis; (c) contacting the extracted Cannabis plantmaterial with a second supercritical fluid solvent system at a suitablepressure (e.g., between about 750 psi and 25,000 psi), and at a suitabletemperature (e.g., between about −15° C. and 200° C.), to provide asecond extract of Cannabis and a second extracted Cannabis plantmaterial; (d) removing the second supercritical fluid solvent systemfrom the second extract of Cannabis; (e) contacting the second extractedCannabis plant material with a third supercritical fluid solvent systemat a suitable pressure (e.g., between about 750 psi and 25,000 psi), andat a suitable temperature (e.g., between about −15° C. and 200° C.), toprovide a third extract of Cannabis and a third extracted Cannabis plantmaterial; and (f) removing the third supercritical fluid solvent systemfrom the third extract of Cannabis.

When the SFE is carried out four times, the FSFE can include: (a)contacting Cannabis with a supercritical fluid solvent system at asuitable pressure (e.g., between about 750 psi and 25,000 psi), and at asuitable temperature (e.g., between about −15° C. and 200° C.), toprovide an extract of Cannabis and an extracted Cannabis plant material;(b) removing the supercritical fluid solvent system from the extract ofCannabis; (c) contacting the extracted Cannabis plant material with asecond supercritical fluid solvent system at a suitable pressure (e.g.,between about 750 psi and 25,000 psi), and at a suitable temperature(e.g., between about −15° C. and 200° C.), to provide a second extractof Cannabis and a second extracted Cannabis plant material; (d) removingthe second supercritical fluid solvent system from the second extract ofCannabis; (e) contacting the second extracted Cannabis plant materialwith a third supercritical fluid solvent system at a suitable pressure(e.g., between about 750 psi and 25,000 psi), and at a suitabletemperature (e.g., between about −15° C. and 200° C.), to provide athird extract of Cannabis and a third extracted Cannabis plant material;(f) removing the third supercritical fluid solvent system from the thirdextract of Cannabis; (g) contacting the third extracted Cannabis plantmaterial with a fourth supercritical fluid solvent system at a suitablepressure (e.g., between about 750 psi and 25,000 psi), and at a suitabletemperature (e.g., between about −15° C. and 200° C.), to provide afourth extract of Cannabis and a fourth extracted Cannabis; and (h)removing the fourth supercritical fluid solvent system from the fourthextract of Cannabis.

Prior to an initial supercritical fluid extraction, the Cannabis may bedried of any water present. Such drying may increase the efficiency ofthe supercritical fluid extraction, or may just lower the cost ofshipping and storage of Cannabis plant material. The Cannabis may beair-dried or dried at an elevated temperature with or without reducedpressure (i.e., in vacuo). Specifically, the Cannabis may be dried invacuo at an elevated temperature. Machines capable of drying Cannabisare known in the art and include an oven, or similar device, such as arotating air drum drier.

For use in the processes of the present invention, the temperature atwhich the Cannabis may be dried can be greater than about 25° C.Specifically, the temperature can be greater than about 30° C., greaterthan about 40° C., or greater than about 50° C. More specifically, thetemperature can be greater than about 60° C., greater than about 70° C.,or greater than about 80° C.

The supercritical fluid extraction can conveniently be carried out at apressure of about 750 psi to about 50,000 psi. It is appreciated thatthose skilled in the art understand that higher pressures may enablefaster extraction. In this case, it may be desirable to subsequentlyseparate and purify the product. Specifically, the pressure may be about1,000 psi to about 50,000 psi, about 1,500 psi to about 40,000 psi,about 2,000 psi to about 35,000 psi, or about 2,500 psi to about 30,000psi. More specifically, the pressure may be about 1,000 psi to about25,000 psi, about 1,000 psi to about 20,000 psi, about 1,000 psi toabout 15,000 psi, or about 1,000 psi to about 10,000 psi. Morespecifically, the pressure may be about 2,000 psi to about 25,000 psi,about 2,000 psi to about 20,000 psi, about 2,000 psi to about 15,000psi, or about 2,000 psi to about 12,000 psi.

For use in the processes of the present invention, the temperature ofsupercritical fluid extraction can conveniently be about 30° C. to about250° C. Specifically, the temperature can be about 30° C. to about 200°C., about 30° C. to about 150° C., or about 30° C. to about 100° C. Morespecifically, the temperature can be about 35° C. to about 200° C.,about 35° C. to about 150° C., or about 35° C. to about 100° C. Morespecifically, the temperature can be about 40° C. to about 200° C.,about 40° C. to about 150° C., or about 40° C. to about 100° C.

For use in the processes of the present invention, the period of time ofsupercritical fluid extraction can conveniently be up to about 24 hours(e.g., about 1 minute to about 24 hours). For example, the period oftime of supercritical fluid extraction can be about 5 minutes to about12 hours, or about 10 minutes to about 1 hour. Specifically, the periodof time of supercritical fluid extraction can be about 5-10 minutes,about 10-20 minutes, about 20-30 minutes, about 30-40 minutes, about40-50 minutes, about 50-60 minutes, about 60-70 minutes, about 70-80minutes, about 80-90 minutes, about 90-100 minutes, etc.

Supercritical fluid extraction employs a solvent (and optionally aco-solvent) which possesses physical properties suitable as asupercritical fluid. Suitable solvents (and co-solvents) useful insupercritical fluid extraction are disclosed, e.g., McHugh, M. AndKrukonis, V., Supercritical Fluid Extraction, 2nd ed,Butterworth-Heinemann, Boston, 1994; Johnston, K. P., Penninger, J. M.L., Supercritical Fluid Science and Technology, ACS Symposium Series406, American Chemical Society, Washington, D.C.; and Taylor, L. T.,Supercritical Fluid Extraction, John Wiley & Sons, New York, 1996.Suitable exemplary solvents (and co-solvents) useful in supercriticalfluid extraction include: carbon dioxide (CO₂), hydrogen (H₂), neon(Ne), nitrogen (N₂), argon (Ar), methane (CH₄), ethane (CH₃CH₃), propane(CH₃CH₂CH₃), ammonia (NH₃), water (H₂O), xenon (Xe), methanol, ethanol,1-propanol, 2-propanol, 1-hexanol, 2-methoxy ethanol, tetrahydrofuran(THF), 1,4-dioxane, acetonitrile, methylene chloride, dichloroethane,chloroform, ethyl acetate, propylene carbonate, N,N-dimethylaceamide,dimethyl sulfoxide (DMSO), formic acid, carbon disulfide, acetone,toluene, hexanes, pentanes, trifluoromethane (Freon® 23), nitrous oxide(N₂O), sulfur hexafluroide (SF₆), butane (n-C₄H₁₀), isobutane (i-C₄H₁₀),ethyl ether ((C₂H₅)₂O), benzotrifluoride (C₆H₅CF₃), (p-chlorophenyl)trifluoromethane (ClC₆H₄CF₃), chlorofluorocarbon (CFC),hydrofluorocarbon (HFA), and HFA-134a (1,1,1,2-tetrafluoroethane).

Typically, when present, the co-solvent will be present in about 1 wt. %to about 50 wt. %, in about 1 wt. % to about 30 wt. %, or in about 1 wt.% to about 10 wt. % of the supercritical fluid solvent system.

The physical properties of carbon dioxide make it particularlyattractive as a solvent for supercritical fluid extraction. Carbondioxide is a major component of the atmosphere and is thereforerelatively safe and abundant. In addition, carbon dioxide is relativelyinexpensive. Compared to most other suitable solvents, carbon dioxide isenvironmentally friendly as it will not harm the atmosphere at thequantities used in the methods of the invention. Moreover, carbondioxide is non-flammable and non-explosive. Further, carbon dioxideleaves no substantial residue or remnant upon evaporation.

Carbon dioxide also possesses physical properties which enable it tochange polarity over the temperature range and pressure range normallyemployed in supercritical fluid extraction. As a result, carbon dioxidemay act as a nonpolar solvent at one temperature and pressure but mayact as a polar solvent at another temperature and pressure. By varyingthe temperature and pressure, the solvent properties may be modified.This allows for the isolation of more than one compound using a singlesolvent system.

The co-solvent can be employed for several practical reasons. Theco-solvent decreases the time necessary for extraction, which decreasesthe costs incurred for the extraction process and increases theefficiency of the extraction process. In addition, the use of at leastone co-solvent decreases the likelihood that the desired compound(s)will crystallize or gum out upon evaporation of the highly volatilesolvent carbon dioxide. When the supercritical fluid extractionapparatus is dismantled and the desired compounds are obtained, thecarbon dioxide will evaporate, leaving the desired crude compounds as asolid or gum-like tar. The use of the co-solvent allows the desiredcompound(s) to remain soluble in a solvent system.

The solvent employed in supercritical fluid extraction may be a singlecompound or may be a mixture of compounds. In addition, the solvent mayinclude an additive. As used herein, an “additive” refers to a substancesuch that upon addition will modify the physical properties of thesolvent. For example, an additive may be useful to modify the polarity,critical temperature, critical pressure, etc., of the solvent system.When present, the additive can be present in about 0.5 wt. % to about 25wt. % of the solvent system, about 0.5 wt. % to about 20 wt. % of thesolvent system, or about 0.5 wt. % to about 15 wt. % of the solventsystem. Specifically, when present, the additive can be present in about1 wt. % to about 15 wt. % of the solvent system, about 1 wt. % to about10 wt. % of the solvent system, or about 1 wt. % to about 5 wt. % of thesolvent system.

Suitable additives include, e.g., lower alcohols (e.g., methanol,ethanol, 1-propanol, 2-propanol, 1-hexanol, or 2-methoxy ethanol);ethers (e.g., tetrahydrofuran or 1,4-dioxane); substituted hydrocarbons(e.g., acetonitrile, dichloromethane, ammonia or chloroform) propylenecarbonate, N,N-dimethylaceamide; dimethyl sulfoxide; carboxylic acids(e.g., formic acid); water; carbon disulfide; lower ketones (e.g.,acetone), hydrocarbons (e.g., propane, toluene, hexanes and pentanes);substituted aromatics (e.g., C₆H₅CF₃, and p-ClC₆H₄CF₃).

The SFE, or any SFE of the FSFE, can be carried out over a suitable andeffective period of time. For use in the processes of the presentinvention, the suitable and effective period of time can be about 10seconds to about 60 minutes. Specifically, the suitable and effectiveperiod of time can be about 20 seconds to about 60 minutes, about 30seconds to about 60 minutes, or about 40 seconds to about 60 minutes.More specifically, the suitable and effective period of time can beabout 10 seconds to about 30 minutes, about 10 seconds to about 20minutes, or about 10 seconds to about 10 minutes. More specifically, thesuitable and effective period of time can be about 20 seconds to about40 minutes, about 30 seconds to about 30 minutes, or about 40 seconds toabout 20 minutes.

Additional conditions (e.g., time, temperature and pressure), solvents,co-solvents, and apparatus, for carrying out the SFE are described,e.g., in U.S. Pat. Nos. 8,501,250; 8,003,144; 7,811,997; 7,368,589;7,214,379; 7,083,748; 6,909,021; 6,773,473; 6,746,695; 6,737,552; and6,576,274.

Cannabis Concentrate

The present invention provides for a pharmaceutical dosage form thatincludes a Cannabis concentrate. The Cannabis concentrate is obtainedfrom the Cannabis extract, which is obtained from the Cannabis plantmaterial. The Cannabis concentrate can include, e.g., cannabinoids,terpenoids, and/or flavonoids. In various embodiments, the Cannabisconcentrate (relative to the starting plant material) can be enrichedwith the desired product (e.g. cannabinoids, terpenoids, and/orflavonoids, or purified fractions in which certain cannabinoid compoundsare enriched or depleted relative to other cannabinoid compounds). Infurther embodiments, the Cannabis concentrate (relative to the startingplant material) can be enriched with one or more specific desiredproducts (e.g. cannabinoids) relative to other desired products (e.g.,terpenoids and/or flavonoids). Additionally, compared to the Cannabisplant material, the Cannabis concentrate can contain a lowerconcentration of unwanted material (e.g. terpenes, alkaloids, hemp oil,and/or cannabinoid acids).

In specific embodiments, the Cannabis concentrate can be enriched interpenoids, flavonoids, and/or cannabinoids. In further specificembodiments, the Cannabis concentrate can be enriched in at least one ofcannabinol (CBN); cannabinolic acid (CBNA); Δ(9)-tetrahydrocannabinol(Δ(9)-THC); Δ(9)-tetrahydrocannabinolic acid (Δ(9)-THCA);Δ(9)-cannabidiol (Δ(9)-CBD); Δ(9)-tetrahydrocannabidiolic acid(Δ(9)-CBDA); Δ(8)-tetrahydrocannabinol (Δ(8)-THC);Δ(8)-tetrahydrocannabinolic acid (Δ(8)-THCA); Δ(8)-tetrahydrocannabidiol(Δ(8)-CBD); Δ(8)-tetrahydrocannabidiolic acid (Δ(8)-CBDA);Δ(9)-tetrahydrocannabivarin (Δ(9)-THV); cannabigerol (CBG);cannabigerolic acid (CBGA); cannabichromene (CBC); cannabichromenic acid(CBCA); cannabicyclol (CBL); cannabicyclolic acid (CBLA);β-caryophyllene epoxide; mentha-1,8(9)-dien-5-ol; pulegone; limonene;limonene oxide; α-terpinene; terpinen-4-ol; carvacrol; carvone;1,8-cineole; p-cymene; fenchone; pulegone-1,2epoxide; β-myrcene;cannaflavin A; and cannaflavin B.

In specific embodiments, the Cannabis concentrate can include atherapeutically effective amount of at least one of cannabinol (CBN);cannabinolic acid (CBNA); Δ(9)-tetrahydrocannabinol (Δ(9)-THC);Δ(9)-tetrahydrocannabinolic acid (Δ(9)-THCA); Δ(9)-cannabidiol(Δ(9)-CBD); Δ(9)-tetrahydrocannabidiolic acid (Δ(9)-CBDA);Δ(8)-tetrahydrocannabinol (Δ(8)-THC); Δ(8)-tetrahydrocannabinolic acid(Δ(8)-THCA); Δ(8)-tetrahydrocannabidiol (Δ(8)-CBD);Δ(8)-tetrahydrocannabidiolic acid (Δ(8)-CBDA);Δ(9)-tetrahydrocannabivarin (Δ(9)-THV); cannabigerol (CBG);cannabigerolic acid (CBGA); cannabichromene (CBC); cannabichromenic acid(CBCA); cannabicyclol (CBL); cannabicyclolic acid (CBLA);β-caryophyllene epoxide; mentha-1,8(9)-dien-5-ol; pulegone; limonene;limonene oxide; α-terpinene; terpinen-4-ol; carvacrol; carvone;1,8-cineole; p-cymene; fenchone; pulegone-1,2epoxide; β-myrcene;cannaflavin A; and cannaflavin B.

In specific embodiments, the Cannabis concentrate can be enriched incannabinol (CBN). In additional specific embodiments, the Cannabisconcentrate can include a therapeutically effective amount of cannabinol(CBN).

In specific embodiments, the Cannabis concentrate can be enriched incannabinolic acid (CBNA). In additional specific embodiments, theCannabis concentrate can include a therapeutically effective amount ofcannabinolic acid (CBNA).

In specific embodiments, the Cannabis concentrate can be enriched inΔ(9)-tetrahydrocannabinol (Δ(9)-THC). In additional specificembodiments, the Cannabis concentrate can include a therapeuticallyeffective amount of Δ(9)-tetrahydrocannabinol (Δ(9)-THC).

In specific embodiments, the Cannabis concentrate can be enriched inΔ(9)-tetrahydrocannabinolic acid (Δ(9)-THCA). In additional specificembodiments, the Cannabis concentrate can include a therapeuticallyeffective amount of Δ(9)-tetrahydrocannabinolic acid (Δ(9)-THCA).

In specific embodiments, the Cannabis concentrate can be enriched inΔ(9)-cannabidiol (Δ(9)-CBD). In additional specific embodiments, theCannabis concentrate can include a therapeutically effective amount ofΔ(9)-cannabidiol (Δ(9)-CBD).

In specific embodiments, the Cannabis concentrate can be enriched inΔ(9)-tetrahydrocannabidiolic acid (Δ(9)-CBDA). In additional specificembodiments, the Cannabis concentrate can include a therapeuticallyeffective amount of Δ(9)-tetrahydrocannabidiolic acid (Δ(9)-CBDA).

In specific embodiments, the Cannabis concentrate can be enriched inΔ(8)-tetrahydrocannabinol (Δ(8)-THC). In additional specificembodiments, the Cannabis concentrate can include a therapeuticallyeffective amount of Δ(8)-tetrahydrocannabinol (Δ(8)-THC).

In specific embodiments, the Cannabis concentrate can be enriched inΔ(8)-tetrahydrocannabinolic acid (Δ(8)-THCA). In additional specificembodiments, the Cannabis concentrate can include a therapeuticallyeffective amount of Δ(8)-tetrahydrocannabinolic acid (Δ(8)-THCA).

In specific embodiments, the Cannabis concentrate can be enriched inΔ(8)-tetrahydrocannabidiol (Δ(8)-CBD). In additional specificembodiments, the Cannabis concentrate can include a therapeuticallyeffective amount of Δ(8)-tetrahydrocannabidiol (Δ(8)-CBD).

In specific embodiments, the Cannabis concentrate can be enriched inΔ(8)-tetrahydrocannabidiolic acid (Δ(8)-CBDA). In additional specificembodiments, the Cannabis concentrate can include a therapeuticallyeffective amount of Δ(8)-tetrahydrocannabidiolic acid (Δ(8)-CBDA).

In specific embodiments, the Cannabis concentrate can be enriched inΔ(9)-tetrahydrocannabivarin (Δ(9)-THV). In additional specificembodiments, the Cannabis concentrate can include a therapeuticallyeffective amount of Δ(9)-tetrahydrocannabivarin (Δ(9)-THV).

In specific embodiments, the Cannabis concentrate can be enriched incannabigerol (CBG). In additional specific embodiments, the Cannabisconcentrate can include a therapeutically effective amount ofcannabigerol (CBG).

In specific embodiments, the Cannabis concentrate can be enriched incannabigerolic acid (CBGA). In additional specific embodiments, theCannabis concentrate can include a therapeutically effective amount ofcannabigerolic acid (CBGA).

In specific embodiments, the Cannabis concentrate can be enriched incannabichromene (CBC). In additional specific embodiments, the Cannabisconcentrate can include a therapeutically effective amount ofcannabichromene (CBC).

In specific embodiments, the Cannabis concentrate can be enriched incannabichromenic acid (CBCA). In additional specific embodiments, theCannabis concentrate can include a therapeutically effective amount ofcannabichromenic acid (CBCA).

In specific embodiments, the Cannabis concentrate can be enriched incannabicyclol (CBL). In additional specific embodiments, the Cannabisconcentrate can include a therapeutically effective amount ofcannabicyclol (CBL).

In specific embodiments, the Cannabis concentrate can be enriched incannabicyclolic acid (CBLA). In additional specific embodiments, theCannabis concentrate can include a therapeutically effective amount ofcannabicyclolic acid (CBLA).

In specific embodiments, the Cannabis concentrate can be enriched inβ-caryophyllene epoxide. In additional specific embodiments, theCannabis concentrate can include a therapeutically effective amount ofβ-caryophyllene epoxide.

In specific embodiments, the Cannabis concentrate can be enriched inmentha-1,8(9)-dien-5-ol. In additional specific embodiments, theCannabis concentrate can include a therapeutically effective amount ofmentha-1,8(9)-dien-5-ol.

In specific embodiments, the Cannabis concentrate can be enriched inpulegone. In additional specific embodiments, the Cannabis concentratecan include a therapeutically effective amount of pulegone.

In specific embodiments, the Cannabis concentrate can be enriched inlimonene. In additional specific embodiments, the Cannabis concentratecan include a therapeutically effective amount of limonene.

In specific embodiments, the Cannabis concentrate can be enriched inlimonene oxide. In additional specific embodiments, the Cannabisconcentrate can include a therapeutically effective amount of limoneneoxide.

In specific embodiments, the Cannabis concentrate can be enriched inα-terpinene. In additional specific embodiments, the Cannabisconcentrate can include a therapeutically effective amount ofα-terpinene.

In specific embodiments, the Cannabis concentrate can be enriched interpinen-4-ol. In additional specific embodiments, the Cannabisconcentrate can include a therapeutically effective amount ofterpinen-4-ol.

In specific embodiments, the Cannabis concentrate can be enriched incarvacrol. In additional specific embodiments, the Cannabis concentratecan include a therapeutically effective amount of carvacrol.

In specific embodiments, the Cannabis concentrate can be enriched incarvone. In additional specific embodiments, the Cannabis concentratecan include a therapeutically effective amount of carvone.

In specific embodiments, the Cannabis concentrate can be enriched in1,8-cineole. In additional specific embodiments, the Cannabisconcentrate can include a therapeutically effective amount of1,8-cineole.

In specific embodiments, the Cannabis concentrate can be enriched inp-cymene. In additional specific embodiments, the Cannabis concentratecan include a therapeutically effective amount of p-cymene.

In specific embodiments, the Cannabis concentrate can be enriched infenchone. In additional specific embodiments, the Cannabis concentratecan include a therapeutically effective amount of fenchone.

In specific embodiments, the Cannabis concentrate can be enriched inpulegone-1,2epoxide. In additional specific embodiments, the Cannabisconcentrate can include a therapeutically effective amount ofpulegone-1,2epoxide.

In specific embodiments, the Cannabis concentrate can be enriched inβ-myrcene. In additional specific embodiments, the Cannabis concentratecan include a therapeutically effective amount of β-myrcene.

In specific embodiments, the Cannabis concentrate can be enriched incannaflavin A. In additional specific embodiments, the Cannabisconcentrate can include a therapeutically effective amount ofcannaflavin A.

In specific embodiments, the Cannabis concentrate can be enriched incannaflavin B. In additional specific embodiments, the Cannabisconcentrate can include a therapeutically effective amount ofcannaflavin B.

In specific embodiments, relative to the Cannabis plant material, theCannabis concentrate can include a higher concentration of cannabinol(CBN). In alternative specific embodiments, relative to the Cannabisplant material, the Cannabis concentrate can include a lowerconcentration of cannabinol (CBN).

In specific embodiments, relative to the Cannabis plant material, theCannabis concentrate can include a higher concentration of cannabinolicacid (CBNA). In alternative specific embodiments, relative to theCannabis plant material, the Cannabis concentrate can include a lowerconcentration of cannabinolic acid (CBNA).

In specific embodiments, relative to the Cannabis plant material, theCannabis concentrate can include a higher concentration ofΔ(9)-tetrahydrocannabinol (Δ(9)-THC). In alternative specificembodiments, relative to the Cannabis plant material, the Cannabisconcentrate can include a lower concentration ofΔ(9)-tetrahydrocannabinol (Δ(9)-THC).

In specific embodiments, relative to the Cannabis plant material, theCannabis concentrate can include a higher concentration ofΔ(9)-tetrahydrocannabinolic acid (Δ(9)-THCA). In alternative specificembodiments, relative to the Cannabis plant material, the Cannabisconcentrate can include a lower concentration ofΔ(9)-tetrahydrocannabinolic acid (Δ(9)-THCA).

In specific embodiments, relative to the Cannabis plant material, theCannabis concentrate can include a higher concentration ofΔ(9)-cannabidiol (Δ(9)-CBD). In alternative specific embodiments,relative to the Cannabis plant material, the Cannabis concentrate caninclude a lower concentration of Δ(9)-cannabidiol (Δ(9)-CBD).

In specific embodiments, relative to the Cannabis plant material, theCannabis concentrate can include a higher concentration ofΔ(9)-tetrahydrocannabidiolic acid (Δ(9)-CBDA). In specific embodiments,relative to the Cannabis plant material, the Cannabis concentrate caninclude a lower concentration of Δ(9)-tetrahydrocannabidiolic acid(Δ(9)-CBDA).

In specific embodiments, relative to the Cannabis plant material, theCannabis concentrate can include a higher concentration ofΔ(8)-tetrahydrocannabinol (Δ(8)-THC). In specific embodiments, relativeto the Cannabis plant material, the Cannabis concentrate can include alower concentration of Δ(8)-tetrahydrocannabinol (Δ(8)-THC).

In specific embodiments, relative to the Cannabis plant material, theCannabis concentrate can include a higher concentration ofΔ(8)-tetrahydrocannabinolic acid (Δ(8)-THCA). In specific embodiments,relative to the Cannabis plant material, the Cannabis concentrate caninclude a lower concentration of Δ(8)-tetrahydrocannabinolic acid(Δ(8)-THCA).

In specific embodiments, relative to the Cannabis plant material, theCannabis concentrate can include a higher concentration ofΔ(8)-tetrahydrocannabidiol (Δ(8)-CBD). In specific embodiments, relativeto the Cannabis plant material, the Cannabis concentrate can include alower concentration of Δ(8)-tetrahydrocannabidiol (Δ(8)-CBD).

In specific embodiments, relative to the Cannabis plant material, theCannabis concentrate can include a higher concentration ofΔ(8)-tetrahydrocannabidiolic acid (Δ(8)-CBDA). In specific embodiments,relative to the Cannabis plant material, the Cannabis concentrate caninclude a lower concentration of Δ(8)-tetrahydrocannabidiolic acid(Δ(8)-CBDA).

In specific embodiments, relative to the Cannabis plant material, theCannabis concentrate can include a higher concentration ofΔ(9)-tetrahydrocannabivarin (Δ(9)-THV). In specific embodiments,relative to the Cannabis plant material, the Cannabis concentrate caninclude a lower concentration of Δ(9)-tetrahydrocannabivarin (Δ(9)-THV).

In specific embodiments, relative to the Cannabis plant material, theCannabis concentrate can include a higher concentration of cannabigerol(CBG). In specific embodiments, relative to the Cannabis plant material,the Cannabis concentrate can include a lower concentration ofcannabigerol (CBG).

In specific embodiments, relative to the Cannabis plant material, theCannabis concentrate can include a higher concentration ofcannabigerolic acid (CBGA). In specific embodiments, relative to theCannabis plant material, the Cannabis concentrate can include a lowerconcentration of cannabigerolic acid (CBGA).

In specific embodiments, relative to the Cannabis plant material, theCannabis concentrate can include a higher concentration ofcannabichromene (CBC). In alternative specific embodiments, relative tothe Cannabis plant material, the Cannabis concentrate can include alower concentration of cannabichromene (CBC).

In specific embodiments, relative to the Cannabis plant material, theCannabis concentrate can include a higher concentration ofcannabichromenic acid (CBCA). In alternative specific embodiments,relative to the Cannabis plant material, the Cannabis concentrate caninclude a lower concentration of cannabichromenic acid (CBCA).

In specific embodiments, relative to the Cannabis plant material, theCannabis concentrate can include a higher concentration of cannabicyclol(CBL). In alternative specific embodiments, relative to the Cannabisplant material, the Cannabis concentrate can include a lowerconcentration of cannabicyclol (CBL).

In specific embodiments, relative to the Cannabis plant material, theCannabis concentrate can include a higher concentration ofcannabicyclolic acid (CBLA). In alternative specific embodiments,relative to the Cannabis plant material, the Cannabis concentrate caninclude a lower concentration of cannabicyclolic acid (CBLA).

In specific embodiments, relative to the Cannabis plant material, theCannabis concentrate can include a higher concentration ofβ-caryophyllene epoxide. In alternative specific embodiments, relativeto the Cannabis plant material, the Cannabis concentrate can include alower concentration of β-caryophyllene epoxide.

In specific embodiments, relative to the Cannabis plant material, theCannabis concentrate can include a higher concentration ofmentha-1,8(9)-dien-5-ol. In alternative specific embodiments, relativeto the Cannabis plant material, the Cannabis concentrate can include alower concentration of mentha-1,8(9)-dien-5-ol.

In specific embodiments, relative to the Cannabis plant material, theCannabis concentrate can include a higher concentration of pulegone. Inalternative specific embodiments, relative to the Cannabis plantmaterial, the Cannabis concentrate can include a lower concentration ofpulegone.

In specific embodiments, relative to the Cannabis plant material, theCannabis concentrate can include a higher concentration of limonene. Inalternative specific embodiments, relative to the Cannabis plantmaterial, the Cannabis concentrate can include a lower concentration oflimonene.

In specific embodiments, relative to the Cannabis plant material, theCannabis concentrate can include a higher concentration of limoneneoxide. In alternative specific embodiments, relative to the Cannabisplant material, the Cannabis concentrate can include a lowerconcentration of limonene oxide.

In specific embodiments, relative to the Cannabis plant material, theCannabis concentrate can include a higher concentration of α-terpinene.In alternative specific embodiments, relative to the Cannabis plantmaterial, the Cannabis concentrate can include a lower concentration ofα-terpinene.

In specific embodiments, relative to the Cannabis plant material, theCannabis concentrate can include a higher concentration ofterpinen-4-ol. In alternative specific embodiments, relative to theCannabis plant material, the Cannabis concentrate can include a lowerconcentration of terpinen-4-ol.

In specific embodiments, relative to the Cannabis plant material, theCannabis concentrate can include a higher concentration of carvacrol. Inalternative specific embodiments, relative to the Cannabis plantmaterial, the Cannabis concentrate can include a lower concentration ofcarvacrol.

In specific embodiments, relative to the Cannabis plant material, theCannabis concentrate can include a higher concentration of carvone. Inalternative specific embodiments, relative to the Cannabis plantmaterial, the Cannabis concentrate can include a lower concentration ofcarvone.

In specific embodiments, relative to the Cannabis plant material, theCannabis concentrate can include a higher concentration of 1,8-cineole.In alternative specific embodiments, relative to the Cannabis plantmaterial, the Cannabis concentrate can include a lower concentration of1,8-cineole.

In specific embodiments, relative to the Cannabis plant material, theCannabis concentrate can include a higher concentration of p-cymene. Inalternative specific embodiments, relative to the Cannabis plantmaterial, the Cannabis concentrate can include a lower concentration ofp-cymene.

In specific embodiments, relative to the Cannabis plant material, theCannabis concentrate can include a higher concentration of fenchone. Inalternative specific embodiments, relative to the Cannabis plantmaterial, the Cannabis concentrate can include a lower concentration offenchone.

In specific embodiments, relative to the Cannabis plant material, theCannabis concentrate can include a higher concentration ofpulegone-1,2epoxide. In alternative specific embodiments, relative tothe Cannabis plant material, the Cannabis concentrate can include alower concentration of pulegone-1,2epoxide.

In specific embodiments, relative to the Cannabis plant material, theCannabis concentrate can include a higher concentration of β-myrcene. Inalternative specific embodiments, relative to the Cannabis plantmaterial, the Cannabis concentrate can include a lower concentration ofβ-myrcene.

In specific embodiments, relative to the Cannabis plant material, theCannabis concentrate can include a higher concentration of cannaflavinA. In alternative specific embodiments, relative to the Cannabis plantmaterial, the Cannabis concentrate can include a lower concentration ofcannaflavin A.

In specific embodiments, relative to the Cannabis plant material, theCannabis concentrate can include a higher concentration of cannaflavinB. In alternative specific embodiments, relative to the Cannabis plantmaterial, the Cannabis concentrate can include a lower concentration ofcannaflavin B.

In specific embodiments, relative to the Cannabis plant material, theCannabis concentrate can include a higher concentration of cannabinoids.In additional specific embodiments, relative to the Cannabis plantmaterial, the Cannabis concentrate can include a lower concentration ofterpenoids. In further specific embodiments, relative to the Cannabisplant material, the Cannabis concentrate can include a higherconcentration of cannabinoids and a lower concentration of terpenoids.

In specific embodiments, relative to the Cannabis plant material, theCannabis concentrate can include a lower concentration of cannabinoids.In additional specific embodiments, relative to the Cannabis plantmaterial, the Cannabis concentrate can include a higher concentration ofterpenoids. In further specific embodiments, relative to the Cannabisplant material, the Cannabis concentrate can include a lowerconcentration of cannabinoids and a higher concentration of terpenoids.

Active Pharmaceutical Ingredient (API)

As described herein, the SFE (or FSFE) can be used to remove unwantedmaterial (e.g. terpenes, alkaloids, hemp oil, and/or cannabinoid acids)from Cannabis plant material. Additionally, the SFE (or FSFE) can beused to obtain a desired product (e.g. cannabinoids, terpenoids, and/orflavonoids) from the Cannabis plant material. Exemplary desired productsnaturally present in Cannabis are illustrated in the table below.

Chemical Name Structural Formula Solubility cannabinol (CBN)

insol. water; sol. MeOH, EtOH, lipids, non-polar organic solventscannabinolic acid (CBNA)

sol water, alkaline solutions; sol. alcohols Water Solubility Estimatefrom Log Kow (WSKOW v1.41): Water Solubility at 25° C. (mg/L): 0.001206Δ(9)-tetrahydrocannabinol (Δ(9)-THC)

0.0028 mg/mL (23° C.) water sol. MeOH, EtOH sol. lipids sol. non-polarorganic solvents Δ(9)- tetrahydrocannabinolic acid (Δ(9)-THCA)

sol water, alkaline solutions; sol. alcohols Δ(9)-cannabidiol (Δ(9)-CBD)

insol. water sol. pentane Δ(9)- tetrahydrocannabidiolic acid (Δ(9)-CBDA)

sol water, alkaline solutions; sol. alcohols Δ(8)-tetrahydrocannabinol(Δ(8)-THC)

insol. water sol. MeOH, EtOH sol. lipids sol. non-polar organic solventsΔ(8)- tetrahydrocannabinolic acid (Δ(8)-THCA)

sol water, alkaline solutions; sol. alcohols Δ(8)-tetrahydrocannabidiol(Δ(8)-CBD)

insol. water sol. pentane Δ(8)- tetrahydrocannabidiolic acid (Δ(8)-CBDA)

sol water, alkaline solutions; sol. alcohols Δ(9)-tetrahydrocannabivarin (Δ(9)-THV)

sol water, alkaline solutions; sol. alcohols cannabigerol (CBG)

insol. water Water Solubility Estimate from Log Kow (WSKOW v1.41): WaterSolubility at 25° C. (mg/L): 0.003756 sol. pentane cannabigerolic acid(CBGA)

sol water, alkaline solutions; sol. alcohols; cannabichromene (CBC)

insol. water sol. pentane cannabichromenic acid (CBCA)

sol water, alkaline solutions; sol. alcohols cannabicyclol (CBL)

insol. water sol. pentane cannabicyclolic acid (CBLA)

sol water, alkaline solutions; sol. alcohols β-caryophyllene epoxide

insol. water sol. alcohols, organic solvents (ethers, halocarbons)mentha-1,8(9)-dien-5-ol

insol. water sol. alcohols, organic solvents (ethers, halocarbons)pulegone

insol. water sol. alcohols, organic solvents (ethers, halocarbons)limonene

insol. water sol. alcohols, organic solvents (ethers, halocarbons,hydrocarbons limonene oxide

insol. water sol. alcohols, organic solvents (ethers, halocarbons)α-terpinene

insol. water sol. alcohols, organic solvents (ethers, halocarbons),hydrocarbons terpinen-4-ol

insol. water sol. alcohols, organic solvents (ethers, halocarbonscarvacrol

sp. sol. water sol. alcohols, organic solvents (ethers, halocarbons)carvone

insol. water sol. alcohols, organic solvents (ethers, halocarbons)1,8-cineole

insol. water sol. alcohols, organic solvents (ethers, halocarbons)p-cymene

insol. water sol. alcohols, organic solvents (ethers, halocarbons),hydrocarbons fenchone

insol. water sol. alcohols, organic solvents (ethers, halocarbons)pulegone-1,2epoxide

insol. water sol. alcohols, organic solvents (ethers, halocarbons)β-myrcene

insol. water sol. alcohols, organic solvents (ethers, halocarbons),hydrocarbons cannaflavin A

insol. water sol. alkalai sol. alcohols, ethers, halocarbons cannaflavinB

insol. water sol. alkalai sol. alcohols, ethers, halocarbons

Oral Thin Film (OTF)

The OTF includes a Cannabis concentrate. Formulation of oral thin filmsinvolves the application of both aesthetic and performancecharacteristics, such as, e.g., strip-forming polymers, plasticizers,active pharmaceutical ingredient, sweetening agents, saliva stimulatingagent, flavoring agents, coloring agents, stabilizing and thickeningagents. From the regulatory perspectives, all excipients used in theformulation of oral drug strips should be approved for use in oralpharmaceutical dosage forms.

The substances can be selected in an amount such that a desireddissolution rate can be targeted. Upon contact with mucosal tissue(including, e.g., oral mucosa) the TF will completely dissolve withinthe desired period of time. The period of time will vary but inreference to the oral cavity, the period of time will typically bewithin about 30-300 seconds.

The OTF can be placed on any suitable surface within the mouth (oralmucosa), including the roof of the mouth, cheek, tongue, and under thetongue (sublingual mucosa).

Dissolving films generally fall into three main classes: fastdissolving, moderate dissolving and slow dissolving. Fast dissolvingfilms generally dissolve in about 1 second to about 30 seconds. Moderatedissolving films generally dissolve in about 1 to about 30 minutes, andslow dissolving films generally dissolve in more than 30 minutes.

The thin film can be manufactured in a manner, employing suitableingredients, such that any one or more of the desired pharmacokineticmetrics (e.g., dose, area under the curve, peak plasma concentration,dosing intervals, time to reach peak plasma concentration, clearance,bioavailability, etc.) are achieved. For example, the thin film can bemanufactured such that the thin film provides for an immediate release(IR) or a time-release (e.g., controlled release (CR), modified release(MR), extended release (ER), or combination thereof) of activeingredient. The thin films described herein therefore possess thepotential to allow the development of sensitive drug targets that mayotherwise not be feasible in tablet or liquid formulations.

The thin film described herein can include a mucoadhesive agent. Themucoadhesive agent, when placed in the oral cavity in contact with themucosa therein, adheres to the mucosa. The mucoadhesive agent isespecially effective in transmucosal delivery of the active ingredient,as the mucoadhesive agent permits a close and extended contact of thecomposition with the mucosal surface by promoting adherence of thecomposition or drug to the mucosa, and facilitates the release of theactive ingredient from the composition. The mucoadhesive agent can be apolymeric compound, such as a cellulose derivative but it may be also anatural gum, alginate, pectin, or such similar polymer. Theconcentration of the mucoadhesive agent in the coating, such as a powdermatrix coating, may be adjusted to vary the length of time that the filmadheres to the mucosa or to vary the adhesive forces generated betweenthe film and mucosa. The mucoadhesive agent may adhere to oral mucosa orto mucosa or tissue in other parts of the body, including the mouth,nose, eyes, vagina, and rectum.

Mucoadhesive agents include, e.g., carboxymethyl cellulose, polyvinylalcohol, polyvinyl pyrrolidone (povidone), sodium alginate, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose,polyethylene glycols, carbopols, polycarbophils, carboxyvinylcopolymers, propylene glycol alginate, alginic acid, methyl methacrylatecopolymers, tragacanth gum, guar gum, karaya gum, ethylene vinylacetate, dimenthylpolysiloxanes, polyoxyalkylene block copolymers,pectin, chitosan, carrageenan, xanthan gum, gellan gum, locust bean gum,and hydroxyethylmethacrylate copolymers.

The thin film described herein can include a flavoring agent. “Flavoringagent” refers to a substance capable of providing a flavor. In additionto providing a palatable and pleasurable factor to the user, theflavoring agent can also mask undesirable flavors present in the OTF.The flavoring agent can include natural flavoring agents (e.g.,extracts).

The thin film described herein can include a flavoring extract. “Flavorextract” refers to a flavoring agent obtained by extracting a part of araw material, e.g., animal or plant material, often by using a solventsuch as ethanol or water. The majority of natural essences are obtainedby extracting the essential oil from the blossoms, fruit, roots, etc.,or the whole plants, through four techniques: expression (when the oilis very plentiful and easily obtained, as in lemon peel), absorption(generally accomplished by steeping in alcohol, as vanilla beans),maceration (used to create smaller bits of the whole, as in makingpeppermint extract, etc.), and distillation (used with maceration, butin many cases, it requires expert chemical knowledge and the erection ofcostly stills).

Flavoring agents can include breath freshening compounds like menthol,spearmint, and cinnamon, coffee beans, other flavors or fragrances suchas fruit (e.g., cherry, orange, grape, etc.) flavors, especially thoseused for oral hygiene, as well as actives used in dental and oralcleansing such as quaternary ammonium bases. The effect of flavors maybe enhanced using flavor enhancers like tartaric acid, citric acid,vanillin, or the like.

The thin film described herein can include a sweetener. “Sweetener”refers to a substance capable of providing a palatable and pleasurablefactor to the user, and/or capable of masking undesirable flavorspresent in the OTF. The sweetener can include one or more artificialsweeteners, one or more natural sweeteners, or a combination thereof.

Artificial sweeteners include, e.g., acesulfame and its various saltssuch as the potassium salt (available as Sunett®), alitame, aspartame(available as NutraSweet® and Equal®), salt of aspartame-acesulfame(available as Twinsweet®), neohesperidin dihydrochalcone, naringindihydrochalcone, dihydrochalcone compounds, neotame, sodium cyclamate,saccharin and its various salts such as the sodium salt (available asSweet'N Low®), stevia, chloro derivatives of sucrose such as sucralose(available as Kaltame® and Splenda®), and mogrosides.

Natural sweeteners include, e.g., glucose, dextrose, invert sugar,fructose, sucrose, glycyrrhizin; monoammonium glycyrrhizinate (soldunder the trade name MagnaSweet®); Stevia rebaudiana (Stevioside),natural intensive sweeteners, such as Lo Han Kuo, polyols such assorbitol, mannitol, xylitol, erythritol, and the like.

The thin film described herein can include a bitter blocker. “Bitterblocker” refers to a substance capable of blocking or diminishing thebitter taste of another substance.

In specific embodiments, the thin film described can be palatable.“Palatable” refers to a substance (e.g., oral thin film) beingrelatively acceptable or agreeable to the palate or taste (e.g., sweetor savory), and in some cases to the olfactory nerves.

The thin film described herein can include a dye, pigment or coloringagent. “Dye or pigment” or “coloring agent” refers to a substance thatimparts coloring and/or aesthetic appearance to the OTF. A dye is acolored substance that has an affinity to the substrate to which it isbeing applied. The dye is generally applied in an aqueous solution, andrequires a mordant to improve the fastness of the dye on the fiber. Apigment is a material that changes the color of reflected or transmittedlight as the result of wavelength-selective absorption. This physicalprocess differs from fluorescence, phosphorescence, and other forms ofluminescence, in which a material emits light. Both dyes and pigmentsappear to be colored because they absorb some wavelengths of light morethan others. In contrast with a dye, a pigment generally is insoluble,and has no affinity for the substrate. Some dyes can be precipitatedwith an inert salt to produce a lake pigment, and based on the salt usedthey could be aluminum lake, calcium lake or barium lake pigments.

One or more dyes, pigments, and coloring agents can be employed in themanufacture of the thin film, such that the thin film has the desiredcolor. Suitable colors include, e.g., white, black, yellow, blue, green,pink, red, orange, violet, indigo, and brown. In specific embodiments,the color of the thin film can indicate the contents (e.g., one or moreactive ingredients) contained therein.

In specific embodiments, the thin film described herein can include apreservative. “Preservative” refers to an agent that extends the storagelife of food and non-food products by retarding or preventingdeterioration of flavor, odor, color, texture, appearance, nutritivevalue, or safety. A preservative need not provide a lethal, irreversibleaction resulting in partial or complete microbial cell destruction orincapacitation. Sterilants, sanitizers, disinfectants, sporicides,viracides and tuberculocidal agents provide such an irreversible mode ofaction, sometimes referred to as “bactericidal” action. In contrast, apreservative can provide an inhibitory or bacteriostatic action that isreversible, in that the target microbes can resume multiplication if thepreservative is removed. The principal differences between apreservative and a sanitizer primarily involve mode of action (apreservative prevents growth rather than killing microorganisms) andexposure time (a preservative has days to months to act whereas asanitizer has at most a few minutes to act).

In specific embodiments, the thin film described herein can have asuitable tensile strength. “Tensile strength” refers to the maximumstress that a material can withstand while being stretched or pulledbefore failing or breaking. Tensile strength is the opposite ofcompressive strength and the values can be quite different. Tensilestrength is defined as a stress, which is measured as force per unitarea. For some non-homogeneous materials (or for assembled components)it can be reported just as a force or as a force per unit width. In theSI system, the unit is the pascal (Pa) (or a multiple thereof, oftenmegapascals (MPa), using the mega-prefix); or, equivalently to pascals,newtons per square meter (N/m²). The customary unit is pounds-force persquare inch (lbf/in² or psi), or kilo-pounds per square inch (ksi, orsometimes kpsi), which is equal to 1000 psi; kilo-pounds per square inchare commonly used for convenience when measuring tensile strengths.Typically, the testing involves taking a small sample with a fixedcross-section area, and then pulling it with a controlled, graduallyincreasing force until the sample changes shape or breaks.

In specific embodiments, the thin film described herein can be pliable.“Pliable” refers to the ability of an article to readily bend, beflexible, or to be supple.

In specific embodiments, the thin film described herein can benon-sticky. “Non-sticky” refers to an article (e.g., thin film) nothaving the property of readily adhering or sticking to another surface(e.g., another article, manufacturing equipment, packaging material, theuser, etc.) while not in use.

In specific embodiments, the thin film described herein can be soft.“Soft” refers to an article being relatively smooth and agreeable to thetouch; not rough or coarse. Such an article will be capable of producingagreeable sensations, pleasant or comfortable, upon contact with ananimal such as a human.

In specific embodiments, the thin film described herein can havechewable configuration. “Chewable configuration” refers to an articlebeing manufactured in such a manner and with ingredients, that itpossesses a configuration capable of being readily chewed by an animal,such as a human.

In specific embodiments, the thin film described herein can have amalleable configuration. “Malleable configuration” refers to refers toan article being manufactured in such a manner and with ingredients,that it possesses a configuration capable of being readily shaped orchanged in form (e.g., folded, bent, rolled, twisted, flexed, etc.)without breaking.

In specific embodiments, the thin film described herein can have aductile property. “Ductile property” refers to the ability of an article(e.g., thin film) being readily shaped or changed in form (e.g., folded,bent, rolled, twisted, flexed, etc.) without breaking.

In specific embodiments, the thin films described herein can beperforated. “Perforated” refers to the one or more holes, apertures orscores existing along a line to facilitate separation. Perforations onthe thin films allow the user to conveniently administer smaller dosagesof the active ingredient. This is especially useful, for example, whenthe patient is a child, who should receive a smaller dosage. Accuratedosing can be metered, e.g., by the weight, size, age, etc. of thepatient.

The OTF serves as an alternative dosage form for patients who experiencedysphagia (difficulty in swallowing) or for where compliance is a knownissue and therefore an easier dosage form to take ensures thatmedication is taken. Additional reasons (and advantages) to use OTFsinclude the convenience of a dosage form that can be taken without wateras well as the inability of the patient to eat or drink (e.g.,experiencing nausea and/or vomiting).

Suitable oral thin films, and methods of preparing oral thin films, aredescribed, e.g., in WO/2012/103464A2; WO/2013/085224A1; US 2013/0039955;US 2011/0305768; WO/2011/072208A1; US 2011/0142942; US 2013/0309294;WO/2012/104834A1; US 2012/0125351; and US 2011/0280925.

Transdermal Patch

The topical adhesive patch includes a backing having a front side and aback side. The patch includes a formulation that is in contact with thefront side of the backing. The formulation includes an adhesive andCannabis concentrate.

Since the backing can be porous and/or vapor permeable, many consumerstypically refer to the device as a “patch,” a “skin patch,” a “topicalpatch,” or an “adhesive skin patch.” As such, the device will herein bereferred interchangeably to as a patch, a skin patch, and/or an adhesiveskin patch. It is appreciated that those skilled in the art understandthat the term “patch” is used to refer to the device and is nototherwise limiting in any manner.

The topical adhesive patch can be manufactured in a manner, employingsuitable ingredients, such that any one or more of the desiredpharmacokinetic metrics (e.g., dose, area under the curve, peak plasmaconcentration, dosing intervals, time to reach peak plasmaconcentration, clearance, bioavailability, etc.) are achieved. Forexample, the topical adhesive patch can be manufactured such that thetopical adhesive patch provides for an immediate release (IR) or atime-release (e.g., controlled release (CR), modified release (MR),extended release (ER), or combination thereof) of active ingredient. Thetopical adhesive patch described herein therefore possess the potentialto allow the development of sensitive drug targets that may otherwisenot be feasible in tablet or liquid formulations.

Backing

The backing is defined by a front side (the side exposed to the subject,or an article of clothing of the subject, during use) and a back side(the side exposed to the environment during use). The backing should benonirritating to human skin. The backing is a self-supporting sheet ofwater soluble or water insoluble, polymeric or natural material thatprovides strength and integrity for the formulation. The backing of theadhesive patch can be vapor permeable. The backing can also be porous,since porosity provides openings for receiving the formulation, and ithelps to assure that the adhesive skin patch is vapor permeable.Specifically, the backing can retain the formulation while allowingmoisture from the skin to pass. Alternatively, the backing can benon-porous. The backing can have any suitable thickness. In specificembodiments, the suitable thickness allows for a flexible, bendable,pliable, vapor permeable, and/or a stretchable sheet of water insolubleporous material. Specifically, the thickness of the backing can be about0.001 mm to about 5.0 mm, about 0.001 mm to about 3.0 mm, or about 0.025mm to about 1.25 mm.

The backing can be manufactured from any suitable material. In specificembodiments, the suitable material forms a flexible, bendable, pliable,and/or stretchable backing. The backing includes a porous or non-poroussheet of water soluble or water insoluble material that provides supportfor the adhesive skin patch. The backing can include water soluble orwater insoluble polymeric fibers, a porous film, or any other kind ofmatrix with spaces within the matrix. A specific backing is alightweight, porous, pliable strip composed of a nonwoven fabric ofpolymeric or natural fibers such as polyester, cotton, or cellulosefibers bonded together with a sizing resin. The backing can be woven ornonwoven. In one embodiment, the backing includes nonwoven fabric.Specifically, the backing can include polyester fibers, polyurethanefibers, polyolefin fibers, polyamide fibers, natural fibers, cottonfibers, copolyester, copolyester fibers, cellulose acetate fibers,polycellulose fibers, or any mixture thereof. Additional stable, waterinsoluble flexible sheet materials and methods for manufacturing thesuitable backings 2 are disclosed, e.g., in U.S. Pat. Nos. 4,675,009;5,536,263; 4,696,854; 5,741,510; and references cited therein, and aresuitable as backings 2 according to the present invention. The infusionof the formulation into the backing can be accomplished, e.g., with theuse of a continuous process mixer, as disclosed, e.g., in U.S. Pat. No.5,536,263, and references cited therein; or as discussed herein.

In a specific embodiment, the backing can be manufactured from asubstance or substances that are generally recognized as safe (GRAS) fortopical use.

The backing can be manufactured from a suitable non-woven fabric that iscommercially available from, e.g., Freudenberg Faservliesstoffe K G(Weinham, Germany); Sontara Technologies (division of DuPontCorporation) (Old Hickory, Tenn.); Lystil S. A. (Brignoud Cedex,France); Dexter Nonwovens (Windsor Locks, Conn.); Testfabrics, Inc.(West Pittiston, Pa.); and Chicopee (New Brusnwick, N.J.). Othercommercial vendors that supply suitable non-woven fabrics can be foundat the Technical Textile website(http://www.technical-textiles.net/technical-textiles-index/orgL.htm).

Alternatively, the fibers of the backing can be interlocked mechanicallyby air or water.

The backing can include a front side and a back side. The adhesive skinpatch can include a formulation located in at least a portion of thefront side of the backing, on at least a portion of the front side ofthe backing, or on and in at least a portion of the front side of thebacking. As such, the formulation can be located on the entire surfaceof the front side of the backing, or the formulation can be located on aportion of the surface of the front side of the backing.

In one embodiment, the formulation can be located on the entire surfaceof the front side of the backing. In addition to being located on thesurface of the front side of the backing, the formulation can be locatedin at least a portion of the underlying surface of the front side of thebacking (e.g., the formulation can be partially embedded into thebacking).

The formulation can penetrate a substantial portion of the front side ofthe backing, as disclosed, e.g., in U.S. Pat. No. 5,536,263, andreferences cited therein. For example, the formulation can penetrateabout one-tenth to about nine-tenths the thickness of the backing, orabout one-fourth to about nine-tenths the thickness of the backing. Assuch, the formulation can be partially embedded into the backing. In oneembodiment, the formulation can be located on the entire front side ofthe backing and partially in the front side of the backing (e.g., theformulation is partially embedded into the backing).

Alternatively, a portion of the front side of the backing can includethe formulation and other portions of the front side of the backing caninclude any suitable and effective combination of the pressure sensitiveadhesive and, optionally, the solvent. For example, a central circularportion of the front side of the backing can include the formulationwhile the remaining portions of the front side of the backing includeonly the pressure sensitive adhesive. The formulation, when partiallyembedded into the front side of the backing, can impart strength andstructure into the adhesive patch. For example, when the formulation ispartially embedded into the backing, the likelihood that the adhesivepatch tears apart when separated from the release liner or when removedfrom the skin after use, is lowered.

When the adhesive skin patch is placed upon the skin of a subject (e.g.,a human), the formulation can be in continuous contact with the skinsurface of the subject.

In one embodiment, the adhesive skin patch, upon contact with skin, canallow the skin to breathe. In one embodiment, the adhesive skin patch,upon prolonged contact with skin, holds in place the formulation, andpermits the skin to breathe over prolonged periods of time typicallyexperienced with the use of the patch, e.g., up to about 7 days, up toabout 24 hours, up to about 12 hours, up to about 8 hours, or up toabout 6 hours.

The adhesive skin patch can be reversibly attached to a release liner.The release liner helps to maintain the adhesiveness of the adhesiveskin patch prior to use, such as during manufacturing, packaging,shipping, and/or storage. Any suitable release liner can be employed foruse in the present invention. Suitable release liners 10 are readilyknown to those of skill in the art. See, e.g., U.S. Pat. Nos. 4,675,009;5,536,263; 4,696,854; 5,741,510; and references cited therein forfurther descriptions of release liners 10 useful in the presentinvention. The release liner can include a perforation that allows thetab section of the release liner to be removed. Removal of the tabsection of the release liner can allow the adhesive skin patch to beremoved from the release liner with relative ease.

The backing can be a porous or non-porous, self-supporting sheet ofwater insoluble or water soluble, polymeric or natural material thatprovides strength and integrity for the formulation. For example, thebacking can be water insoluble polymeric fibers, open cell foam backing(e.g., polyurethane, polyvinyl chloride, or polyethylene), a porousfilm, or any other kind of matrix with spaces within the matrix. In oneembodiment, the backing can include polyester, polyurethane, polyolefin,polyamide fibers, natural fibers, cotton fibers, polycellulose fibers,or any mixture thereof.

The back side of the backing of the patch can be relatively dry to thetouch, such that upon contact, e.g., with a skin surface or article ofclothing, no appreciable or significant amount of liquid, gel, ointment,fluid, lotion, and the like, present in the back side of the backing ofthe patch is transferred there from and deposited upon the skin surfaceor article of clothing.

The back side of the backing of the patch can have a relatively smalldegree of moisture, while still being considered a “dry” patch, andwould still be relatively dry to the touch, such that upon contact,e.g., with a skin surface or article of clothing, no appreciable orsignificant amount of liquid, gel, ointment, fluid, lotion, and thelike, present in the back side of the backing of the patch istransferred there from and deposited upon the skin surface or article ofclothing.

In one embodiment, the back side of the backing of the patch can berelatively dry, upon touching.

Formulation

The patch can include a formulation that includes the Cannabisconcentrate and adhesive, and optionally any one or more of a skinpenetration enhancer, solvent, adhesive, polymer, humectant, topicalmoisturizer, polyhydric alcohol, and water.

The backing can include a front side and a back side. The patch caninclude a formulation located in at least a portion of the front side ofthe backing, located on at least a portion of the front side of thebacking, or located on and in at least a portion of the front side ofthe backing. In one embodiment, the formulation is located on the entirefront side of the backing and partially in the front side of the backing(e.g., the formulation is partially embedded into the backing).

The formulation can be positioned on and in any portion of the frontside of the backing, i.e., the formulation can be positioned on at leasta portion on the front side of the backing, in at least a portion on thefront side of the backing, or on and in at least a portion on the frontside of the backing. The formulation can be positioned in a portion ofthe front side of the backing (e.g., the formulation penetrates asubstantial portion of the front side of the backing) as disclosed in,e.g., U.S. Pat. No. 5,536,263, and references cited therein. Forexample, the formulation can penetrate a substantial portion of thefront side of the backing, e.g., typically between about one-fourth toabout nine-tenths the thickness of the backing.

In one embodiment, the formulation can be positioned on the entire frontside of the backing. In this latter configuration, the formulation is incontinuous contact with the entire front side of the backing. When theadhesive skin patch is placed upon the skin surface of a subject, theformulation is in continuous contact with the skin surface of thesubject.

Alternatively, a portion of the front side of the backing can containthe formulation and other portions of the front side of the backing cancontain any combination of the adhesive, and, optionally, the solvent.For example, a central circular portion of the front side of the backingcan contain the formulation while the remaining portions of the frontside of the backing contains only the adhesive.

The formulation can include a Cannabis concentrate and an adhesive, andoptionally one or more of the following components: a solvent, one ormore polymers, a humectant, a topical moisturizer, and one or morepolyhydric alcohols.

The formulation can remain stable over the period of time typicallyexperienced with the manufacturing, packaging, shipping, and/or storageof the adhesive skin patch, e.g., up to about a month, up to about ayear, or up to about two years.

Solvent

The solvent can act as a carrier for, and in one embodiment, candissolve, the adhesive. Any suitable solvent can be employed, providedthe solvent effectively and independently dissolves the adhesive, andthe solvent remains stable in the formulation. In one embodiment, thestability is over a prolonged period of time, e.g., up to about 2 years,up to about 1 year, or up to about 6 months, typically experienced inthe manufacturing, packaging, shipping, and/or storage of the patch.

The solvent can include one or more organic compounds, one or moreinorganic compounds, or mixtures thereof. In one embodiment, the solventwill include one or more organic compounds, e.g., esters, alcohols,ketones, aldehydes, fatty acids, partially or fully esterified fattyacids, wherein the structures are cyclic, non-cyclic (e.g., alkyl),alicyclic (e.g., a bridged ring compound) or aromatic, as well asorganic compounds having combinations of these functional groups.Suitable exemplary solvents are disclosed, e.g., in Aldrich Handbook ofFine Chemicals, 2000-2001 (Milwaukee, Wis.). In one embodiment, thesolvent includes water (e.g., deionized water).

In one embodiment of the present invention, the solvent can include a(C₁-C₁₂) acyclic hydrocarbon, a (C₃-C₁₂) cyclic hydrocarbon, a (C₆-C₁₂)aryl hydrocarbon, a (C₆-C₁₂) heteroaryl hydrocarbon, or a (C₃-C₁₂)heterocyclic hydrocarbon;

wherein any of the hydrocarbons can optionally include one or morecarbon-carbon double bonds and any of the hydrocarbons can optionallyinclude one or more carbon-carbon triple bonds;

wherein any of the hydrocarbons can optionally include one or more oxy(—O—), carbonyl (—C(═O)C—), carboxylato (—C(═O)O—), dioxy (—O—O—),dithio (—S—S—), imino (—NH—), methylene dioxy (—OCH₂O—), sulfinyl(—SO—), sulfonyl (—SO₂—), or thio (—S—);

wherein any of the hydrocarbons can optionally be substituted with oneor more amino, hydroxyl, cyano, nitro, (C₁-C₁₂)alkoxy, halo, trifluoro,trifluoro (C₁-C₁₂)alkyl, NR¹R², or COOR¹; wherein R¹ and R² are eachindependently hydrogen, a (C₁-C₁₂) acyclic hydrocarbon or a (C₃-C₁₂)cyclic hydrocarbon.

The solvent can be employed in any suitable amount, provided the amountof solvent is effective to independently dissolve the adhesive and theeffective amount of solvent remains stable in the formulation. In oneembodiment, the stability is over a prolonged period of time, e.g., upto about 2 years, up to about 1 year, or up to about 6 months, typicallyexperienced in the manufacturing, packaging, shipping, and/or storage ofthe patch.

In a specific embodiment, the nature and amount of the solvent isselected, such that it will be generally recognized as safe (GRAS) fortopical use.

Adhesive

Any suitable adhesive can be employed, provided the adhesive providesthe requisite adhesiveness to the patch and the adhesive remains stablein the formulation. In one embodiment, the stability is over a prolongedperiod of time, e.g., up to about 2 years, up to about 1 year, or up toabout 6 months, typically experienced in the manufacturing, packaging,shipping, and/or storage of the patch. It is appreciated that thesuitable adhesives would be known to those skilled in the art. Suitableadhesives are disclosed, e.g., in U.S. Pat. No. 4,675,009; U.S. Pat. No.5,536,263; U.S. Pat. No. 4,696,854; U.S. Pat. No. 5,741,510, andreferences cited therein. In one embodiment the adhesive is an acrylicester copolymer.

Any suitable amount of adhesive can be employed, provided the amount ofadhesive effectively provides the requisite adhesiveness to the patchand the effective amount of the adhesive remains stable in theformulation over a prolonged period of time. Typically, the suitableamount of adhesive depends upon the specific adhesive or adhesivesemployed. The formulation can include an adhesive in about 0.1 wt. % toabout 50 wt. % of the formulation. In one embodiment, the formulationcan include an adhesive in about 0.5 wt. % to about 10.0 wt. % of theformulation. In one embodiment, the formulation can include an adhesivein about 1.0 wt. % to about 15.0 wt. % of the formulation.

Alternatively, the adhesive can include a hot melt pressure sensitiveadhesive or solvent based pressure sensitive adhesive (e.g.,polyacrylate, polyisobutylene, and polybutene), rubber, silicone basedpressure sensitive adhesives (e.g., polydimethylsiloxane and resinmixtures), polystyrene-polybutadiene-polystyrene,polystyrene-polyisoprene-polystyrene,polystyrene-poly(ethylene-butylene)-polystyrene block polymers, or anycombination thereof. In addition, the adhesive can include a resinemulsion adhesive, wherein the resin emulsion adhesive can include vinylacetate resin, acrylic ester copolymer, vinyl actetate/diocyl maleatecopolymer, acrylic copolymer, or any combination thereof.

Other suitable adhesives are disclosed, e.g., in U.S. Pat. Nos.4,675,009; 5,536,263; 4,696,854; 5,741,510; and references citedtherein.

The adhesive can be located on and in any portion of the formulation. Inone embodiment, the adhesive can be located on the entire skin contactside of the formulation. When the adhesive skin patch is placed upon theskin surface of a subject, the adhesive in this configuration is incontinuous contact with the skin surface of the subject.

In a specific embodiment, the nature and amount of the adhesive isselected, such that it will be generally recognized as safe (GRAS) fortopical use.

Polymers

The formulation can optionally include one or more polymers. The polymerprovides structure and strength to the adhesive or can contain andrelease the active agent in a second formulation. Any suitable polymercan be employed, provided the polymer provides structure and strength tothe adhesive and the polymer remains stable in the formulation. In oneembodiment, the stability is over a prolonged period of time, e.g., upto about 2 years, up to about 1 year, or up to about 6 months, typicallyexperienced in the manufacturing, packaging, shipping, and/or storage ofthe patch.

The suitable amount of polymer can depend upon the specific polymer orpolymers employed. For example, gum karaya can be employed as thepolymer in about 10 wt. % to about 55 wt. % of the formulation, in about20 wt. % to about 35 wt. % of the formulation, or in about 23 wt. % toabout 29 wt. % of the formulation. In one embodiment, gum karaya can beemployed as the polymer in about 24 wt. % to about 28 wt. % of theformulation.

Suitable polymers include, e.g., starch, starch derivatives, polyvinylpyrrolidone, polyethylene oxide, polyacrylate quats, polymaleic acid,polymaleic anhydride, polyurethanes, polyureas, gum karaya, gum acacia,locust bean gum, xanthan gum, guar gum, modified guar gum, maltodextrin,carboxymethyl cellulose, carboxypropyl cellulose, polyacrylamide,polyvinyl alcohol, poly AMPS, and polyacrylates. Other suitable polymersare disclosed, e.g., in U.S. Pat. Nos. 4,675,009; 5,536,263; 4,696,854;5,741,510; and references cited therein. In one embodiment, the polymeris gum karaya. The term “gum karaya” refers to a vegetable gum producedas an exudate by trees of the genus Sterculia. Chemically, gum karaya isan acid polysaccharide composed of the sugars galactose, rhamnose, andgalacturonic acid.

In a specific embodiment, the nature and amount of the polymer isselected, such that it will be generally recognized as safe (GRAS) fortopical use.

Humectant

The formulation can optionally include one or more humectants to providea moistening effect to the adhesive. For example, the humectant canhydrate the polymer. Any suitable humectant can be employed, providedthe humectant effectively provides a moistening effect to the adhesiveand the humectant remains stable in the formulation. In one embodiment,the stability is over a prolonged period of time, e.g., up to about 2years, up to about 1 year, or up to about 6 months, typicallyexperienced in the manufacturing, packaging, shipping, and/or storage ofthe patch. One suitable humectant is glycerin. Other suitable humectantsinclude polyhydric alcohols such as ethylene glycol, propylene glycol,triethylene glycol, tetraethylene glycol, and sorbitol.

Any suitable amount of humectant can be employed, provided the amount ofhumectant effectively provides a moistening effect to the adhesive andthe effective amount of humectant remains stable in the formulation. Thesuitable amount of humectant can depend upon the specific humectant orhumectants employed and the specific polymer or polymers employed. Forexample, gum karaya can be employed as the polymer and glycerin can beemployed as the humectant in about 20 wt. % to about 70 wt. % of theformulation, and in one embodiment about 30 wt. % to about 60 wt. % ofthe formulation, or about 40 wt. % to about 50 wt. % of the formulation.

In a specific embodiment, the nature and amount of the humectant isselected, such that it will be generally recognized as safe (GRAS) fortopical use.

Topical Moisturizer

The formulation can optionally include a topical moisturizer (e.g., skinprotectant). Any suitable topical skin protectant can be employed,provided the skin is effectively protected or moisturized and the skinprotectant remains stable in the formulation. In one embodiment, thestability is over a prolonged period of time, e.g., up to about 2 years,up to about 1 year, or up to about 6 months, typically experienced inthe manufacturing, packaging, shipping, and/or storage of the patch.Suitable skin protectants include, e.g. aloe, lanolin, glycerin,calamine, Vitamin E, Vitamin E acetate, Vitamin C, allantoin, aluminumhydroxide gel, bismuth subnitrate, boric acid, calamine, cocoa butter,dimethicone, glycerin, kaolin, live yeast cell derivative, petrolatum,pyridoxine hydrochloride, shark liver oil, sodium bicarbonate, sulfur,tannic acid, topical starch, trolamine, white petrolatum, zinc acetate,zinc carbonate zinc oxide, zinc sulfate, shea butter, and anycombination thereof.

As used herein, calamine is a pink powder of zinc oxide and a skinprotectant containing about 98% zinc oxide and about 0.5% ferric oxide;aloe is the dried latex of leaves of Curaco Aloe (Aloe barbadenisMiller, Aloe vera Linne) or Cape Aloe (Aloe ferox Miller and hybrids),of the family Liliacaea; Vitamin E is3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzopy-ran-6-ol;Vitamin E acetate is3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzopy-ran-6-olacetate; and lanolin is the fat-like secretion of the sebaceous glandsof sheep (i.e., complex mixture of esters and polyesters of 33 highmolecular weight alcohols and 36 fatty acids) which is deposited ontothe wool fibers. In one embodiment, the topical moisturizer can be aloeand Vitamin E.

Aloe is commercially available as Aloe Vera Gel from Terry Laboratories(Melbourne, Fla.). Aloe Vera Gel is commercially available as Aloe VeraGel 40.times. (20.0 wt. % solution in water), Aloe Vera Gel 1.times.(0.5 wt. % solution in water), Aloe Vera Gel (5.0 wt. % solution inwater), or solid Aloe Vera. The solid Aloe Vera can be dissolved in acarrier, such as water, to the desired concentration. In addition, thecommercially available forms of Aloe Vera are optionally available asdecolorized Aloe Vera.

Any suitable amount of topical moisturizer can be employed, provided thesuitable amount of topical moisturizer or skin protectant effectivelyprotects or moisturizes the skin and the effective amount of skinprotectant remains stable in the formulation over a prolonged period oftime. The suitable and effective amount of topical moisturizer candepend in part upon the specific moisturizer or moisturizers present inthe formulation. For example, Aloe Vera Gel can be present up to about40.0 wt. % of the formulation. In one embodiment, Aloe Vera Gel can bepresent up to about 5.0 wt. % of the formulation. In one embodiment,Aloe Vera Gel can be present up to about 1.0 wt. % of the formulation.In addition, Vitamin E acetate can be present up to about 5 wt. % of theformulation. In one embodiment, Vitamin E acetate can be present up toabout 1.0 wt. % of the formulation. In one embodiment, Vitamin E acetatecan be present up to about 0.5 wt. % of the formulation.

In a specific embodiment, the nature and amount of the topicalmoisturizer is selected, such that it will be generally recognized assafe (GRAS) for topical use.

Polyhydric Alcohol

The formulation can optionally include one or more polyhydric alcohols.Suitable polyhydric alcohols include, e.g., ethylene glycol, propyleneglycol, triethylene glycol, tetraethylene glycol, sorbitol, or anycombination thereof. Specifically, the polyhydric alcohol can includepropylene glycol.

Any suitable amount of polyhydric alcohol can be employed. For example,when present in the formulation, the polyhydric alcohol can be presentup to about 35 wt. % of the formulation, up to about 15 wt. % of theformulation, or up to about 5 wt. % of the formulation. In oneembodiment, the polyhydric alcohol can be present in about 0.5 wt. % toabout 5.0 wt. % of the formulation.

Water

The formulation can optionally include water, e.g., deionized water(DI). Any suitable amount of water can be employed, provided the amountof water maintains the adhesiveness of the adhesive and maintains theappropriate stability of the formulation. For example, deionized watercan be present up to about 50 wt. % of the formulation, up to about 40.0wt. % of the formulation, or up to about 30.0 wt. % of the formulation.In one embodiment, deionized water can be present up to about 20.0 wt. %of the formulation. In one embodiment, deionized water can be present upto about 10.0 wt. % of the formulation. In one embodiment, deionizedwater can be present in about 5.0 wt. % to about 15.0 wt. % of theformulation.

Skin Penetration Enhancer

The formulation can optionally include a skin penetration enhancer (orskin permeation enhancer). Any skin penetration enhancer can beemployed, provided the skin penetration enhancer is safe (e.g., is onthe GRAS list) and effectively facilitates the passage of Cannabisconcentrate (or any desired substances contained therein) across theskin membrane. Suitable skin penetration enhancers include, e.g.,dimethyl sulphoxide (DMSO), monoglycerides, C₁₀-C₂₀ fatty acid estersincluding ethyl palmitate and isopropyl myristate; acyl lactylates suchas caproyl lactylic acid and lauroyl lactylic acid; dimethyl lauramide;dodecyl (lauryl) acetate; lactate esters such as lauryl lactate, andmyristyl lactate; monoalkyl ethers of polyethyleneglycol and their alkylor aryl carboxylic acid esters and carboxymethyl ethers such aspolyethylene glycol-4 lauryl ether (Laureth-4) and polyethylene glycol-2lauryl ether (Laureth-2); Myreth-3, myristyl sarcosine, and methyllaurate; polypropylene glycol, polyethylene glycol, lecithin, urea,amino acids, 1-dodecylhexahydro-2H-azepine 2-one (Azone), oleic acid,linoleic acid, isopropyl linoleate, oleyl alcohol,1-dodecyl-azacycloheptan-2-one, and butanediol.

Any suitable amount of skin penetration enhancer can be employed,provided the amount of skin penetration enhancer facilitates the passageof Cannabis concentrate (or any desired substances contained therein)across the skin membrane. For example, the skin penetration enhancer canbe present up to about 50 wt. % of the formulation, up to about 40.0 wt.% of the formulation, or up to about 30.0 wt. % of the formulation. Inone embodiment, the skin penetration enhancer can be present up to about20.0 wt. % of the formulation. In one embodiment, the skin penetrationenhancer can be present up to about 10.0 wt. % of the formulation. Inone embodiment, the skin penetration enhancer can be present in about0.25 wt. % to about 15.0 wt. % of the formulation.

The Patch

The adhesive skin patch can have any suitable size and shape. Inaddition, the adhesive skin patch can be cut, as desired, to provide anadhesive skin patch of a suitable size and shape. The adhesive skinpatch can be cut with any suitable cutting device such as a scissors,scalpel, or knife.

In one embodiment, the adhesive skin patch has a length of about 0.1inch to about 12 inches (about 2.54 mm to about 304.8 mm), about 0.1inch to about 8 inches (about 2.54 mm to about 203.2 mm), of about 0.20inch to about 4 inches (about 5.08 mm to about 101.6 mm), or about 0.2inches to about 2.0 inches (about 5.08 mm to about 50.8 mm). In oneembodiment, the adhesive skin patch has a length of about 1.0 inch toabout 8 inches (about 25.4 mm to about 203.2 mm), about 2 inches (about50.8 mm to about 152.4 mm) to about 6 inches (about 5.08 mm to about152.4 mm), or about 3 inches to about 4 inches (about 76.2 mm to about101.6 mm).

In one embodiment, the adhesive skin patch has a width of about 0.1 inchto about 12.0 inches (about 2.54 mm to about 304.8 mm), about 0.1 inchto about 4 inches (about 2.54 mm to about 101.6 mm), about 0.20 inchesto about 2.0 inches (about 5.08 mm to about 50.8 mm), or about 0.2inches to about 1.0 inch (about 5.08 mm to about 25.4 mm). In oneembodiment, the adhesive skin patch has a width of about 1.0 inch toabout 8 inches (about 25.4 mm to about 203.2 mm), about 2 inches toabout 6 inches (about 50.8 to about 152.4 mm), or about 3 inches toabout 4 inches (about 76.2 mm to about 101.6 mm).

In one specific embodiment of the present invention, the adhesive skinpatch can be oval or elliptical in shape. The oval or elliptical patchcan have a length of about 0.25 inches to about 0.50 inches (6.35 mm toabout 12.7 mm) and a width of about 0.25 inches to about 0.50 inches(6.35 mm to about 12.7 mm). In another specific embodiment of thepresent invention, the adhesive skin patch can have a circular shape.The circular patch can have a diameter of about 0.25 inches to about0.50 inches (6.35 mm to about 12.7 mm).

In one embodiment, the adhesive skin patch can be individually wrapped.Some consumers have shown a preference for adhesive skin patches thatare individually wrapped. The individually wrapped adhesive skin patchoffers to the consumer the ability and convenience of being able tocarry a few (e.g., 1, 2, or 3) adhesive skin patches that are eachindividually wrapped. In such an embodiment, the use of one patch willnot compromise the cleanliness and/or sterility of the remainingpatches. Alternatively, more than one adhesive skin patch can be wrappedtogether. For example, 2 to about 20, 2 to about 15, or 2 to about 10adhesive skin patches can be wrapped together. The cost of suchpackaging and wrapping can be decreased, compared to skin patches thatare individually wrapped. In one specific embodiment, the adhesive skinpatch can be individually wrapped as a right and left handed pair. Thecost of having two or more patches wrapped together is typically lessexpensive than skin patches that are individually wrapped.

In one embodiment of the present invention, the adhesive patch issterile. The adhesive patch can be sterilized by any suitable meansknown to those of skill in the art. For example, the adhesive patch ofthe present invention can be sterilized by irradiation. Specifically,the adhesive patch of the present invention can be sterilized byterminal irradiation (e.g., when the adhesive patch of the presentinvention is in the package).

Production of the Patch

The adhesive patch of the present invention can be formulated ormanufactured employing the above components. The adhesive patch of thepresent invention can be formulated or manufactured using any suitabletechnique. In one embodiment, the adhesive patch can be formulated ormanufactured as described in U.S. Pat. Nos. 5,536,263; 5,741,510; andreferences cited therein.

The adhesive patch can be applied to any skin surface of a subject. Thesubject can be a human (e.g., child that is younger than 18 years ofage). The adhesive patch can be applied by the subject, or by anotherperson (e.g., parent, nurse, or physician).

Additional transdermal patches, and methods of preparing transdermalpatches, are described, e.g., in US 2009/0028929; WO/2012/026829A1; US2013/0220846; U.S. Pat. No. 8,095,213; U.S. Pat. No. 5,948,433; US2014/0031770; WO/2013/027681A1; WO/2012/105624A1; WO/2008/008135A1; US2008/0008747; WO/2008/133982A2; EP0674913A2; WO/2000/069405A1; U.S. Pat.No. 5,536,263; U.S. Pat. No. 5,741,510; U.S. Pat. No. 6,096,334; and US2011/0293681.

Specific Ranges, Values, and Embodiments

Specific ranges, values, and embodiments provided below are forillustration purposes only and do not otherwise limit the scope of theinvention, as defined by the claims. The specific ranges, values, andembodiments described below encompass all combinations andsub-combinations of each disclosed range, value, and embodiment, whetheror not expressly described as such

Solvent System

When the SFE is carried out one time, the SFE can include: (i) a polarprotic solvent system, (ii) a polar aprotic solvent system, (iii) anonpolar protic solvent system, or (iv) a nonpolar aprotic solventsystem.

In specific embodiments, the SFE is carried out one time, wherein theSFE includes a solvent systems illustrated in any one of 1-4 below.

No. SFE solvent system 1 polar protic 2 polar aprotic 3 nonpolar protic4 nonpolar aprotic

When the SFE is carried out two times, each FSFE can independentlyinclude: (i) a polar protic solvent system, (ii) a polar aprotic solventsystem, (iii) a nonpolar protic solvent system, or (iv) a nonpolaraprotic solvent system.

In specific embodiments, the SFE is carried out two times, wherein thefirst and second FSFEs include solvent systems illustrated in any one of1-16 below. When the first and second FSFEs include solvent systemshaving the same combination of polarity and proticity (e.g., both thefirst and second FSFEs include polar aprotic solvent systems), thoseFSFEs will typically be carried out at a different temperature and/orpressure.

First FSFE Second FSFE No. solvent system solvent system 1 polar proticpolar protic 2 polar protic polar aprotic 3 polar protic nonpolar protic4 polar protic nonpolar aprotic 5 polar aprotic polar protic 6 polaraprotic polar aprotic 7 polar aprotic nonpolar protic 8 polar aproticnonpolar aprotic 9 nonpolar protic polar protic 10 nonpolar protic polaraprotic 11 nonpolar protic nonpolar protic 12 nonpolar protic nonpolaraprotic 13 nonpolar aprotic polar protic 14 nonpolar aprotic polaraprotic 15 nonpolar aprotic nonpolar protic 16 nonpolar aprotic nonpolaraprotic

When the SFE is carried out three times, each FSFE can independentlyinclude: (i) a polar protic solvent system, (ii) a polar aprotic solventsystem, (iii) a nonpolar protic solvent system, or (iv) a nonpolaraprotic solvent system.

In specific embodiments, the SFE is carried out three times, wherein thefirst, second and third FSFEs include solvent systems illustrated in anyone of 1-64 below. When at least two of the first, second and thirdFSFEs include solvent systems having the same combination of polarityand proticity (e.g., both the second and third FSFEs include polaraprotic solvent systems), those FSFEs will typically be carried out at adifferent temperature and/or pressure.

First FSFE Second FSFE Third FSFE No. solvent system solvent systemsolvent system 1 polar protic polar protic polar protic 2 polar proticpolar protic polar aprotic 3 polar protic polar protic nonpolar protic 4polar protic polar protic nonpolar aprotic 5 polar protic polar aproticpolar protic 6 polar protic polar aprotic polar aprotic 7 polar proticpolar aprotic nonpolar protic 8 polar protic polar aprotic nonpolaraprotic 9 polar protic nonpolar protic polar protic 10 polar proticnonpolar protic polar aprotic 11 polar protic nonpolar protic nonpolarprotic 12 polar protic nonpolar protic nonpolar aprotic 13 polar proticnonpolar aprotic polar protic 14 polar protic nonpolar aprotic polaraprotic 15 polar protic nonpolar aprotic nonpolar protic 16 polar proticnonpolar aprotic nonpolar aprotic 17 polar aprotic polar protic polarprotic 18 polar aprotic polar protic polar aprotic 19 polar aproticpolar protic nonpolar protic 20 polar aprotic polar protic nonpolaraprotic 21 polar aprotic polar aprotic polar protic 22 polar aproticpolar aprotic polar aprotic 23 polar aprotic polar aprotic nonpolarprotic 24 polar aprotic polar aprotic nonpolar aprotic 25 polar aproticnonpolar protic polar protic 26 polar aprotic nonpolar protic polaraprotic 27 polar aprotic nonpolar protic nonpolar protic 28 polaraprotic nonpolar protic nonpolar aprotic 29 polar aprotic nonpolaraprotic polar protic 30 polar aprotic nonpolar aprotic polar aprotic 31polar aprotic nonpolar aprotic nonpolar protic 32 polar aprotic nonpolaraprotic nonpolar aprotic 33 nonpolar protic polar protic polar protic 34nonpolar protic polar protic polar aprotic 35 nonpolar protic polarprotic nonpolar protic 36 nonpolar protic polar protic nonpolar aprotic37 nonpolar protic polar aprotic polar protic 38 nonpolar protic polaraprotic polar aprotic 39 nonpolar protic polar aprotic nonpolar protic40 nonpolar protic polar aprotic nonpolar aprotic 41 nonpolar proticnonpolar protic polar protic 42 nonpolar protic nonpolar protic polaraprotic 43 nonpolar protic nonpolar protic nonpolar protic 44 nonpolarprotic nonpolar protic nonpolar aprotic 45 nonpolar protic nonpolaraprotic polar protic 46 nonpolar protic nonpolar aprotic polar aprotic47 nonpolar protic nonpolar aprotic nonpolar protic 48 nonpolar proticnonpolar aprotic nonpolar aprotic 49 nonpolar aprotic polar protic polarprotic 50 nonpolar aprotic polar protic polar aprotic 51 nonpolaraprotic polar protic nonpolar protic 52 nonpolar aprotic polar proticnonpolar aprotic 53 nonpolar aprotic polar aprotic polar protic 54nonpolar aprotic polar aprotic polar aprotic 55 nonpolar aprotic polaraprotic nonpolar protic 56 nonpolar aprotic polar aprotic nonpolaraprotic 57 nonpolar aprotic nonpolar protic polar protic 58 nonpolaraprotic nonpolar protic polar aprotic 59 nonpolar aprotic nonpolarprotic nonpolar protic 60 nonpolar aprotic nonpolar protic nonpolaraprotic 61 nonpolar aprotic nonpolar aprotic polar protic 62 nonpolaraprotic nonpolar aprotic polar aprotic 63 nonpolar aprotic nonpolaraprotic nonpolar protic 64 nonpolar aprotic nonpolar aprotic nonpolaraprotic

When the SFE is carried out four times, each FSFE can independentlyinclude: (i) a polar protic solvent system, (ii) a polar aprotic solventsystem, (iii) a nonpolar protic solvent system, or (iv) a nonpolaraprotic solvent system.

In specific embodiments, the SFE is carried out four times, wherein thefirst, second, third and fourth FSFEs include solvent systemsillustrated in any one of 1-256 below. When at least two of the first,second, third and fourth FSFEs include solvent systems having the samecombination of polarity and proticity (e.g., both the third and fourthFSFEs include polar aprotic solvent systems), those FSFEs will typicallybe carried out at a different temperature and/or pressure.

First FSFE Second FSFE Third FSFE Fourth FSFE No. solvent system solventsystem solvent system solvent system 1 polar protic polar protic polarprotic polar protic 2 polar protic polar protic polar protic polaraprotic 3 polar protic polar protic polar protic nonpolar protic 4 polarprotic polar protic polar protic nonpolar aprotic 5 polar protic polarprotic polar aprotic polar protic 6 polar protic polar protic polaraprotic polar aprotic 7 polar protic polar protic polar aprotic nonpolarprotic 8 polar protic polar protic polar aprotic nonpolar aprotic 9polar protic polar protic nonpolar protic polar protic 10 polar proticpolar protic nonpolar protic polar aprotic 11 polar protic polar proticnonpolar protic nonpolar protic 12 polar protic polar protic nonpolarprotic nonpolar aprotic 13 polar protic polar protic nonpolar aproticpolar protic 14 polar protic polar protic nonpolar aprotic polar aprotic15 polar protic polar protic nonpolar aprotic nonpolar protic 16 polarprotic polar protic nonpolar aprotic nonpolar aprotic 17 polar proticpolar aprotic polar protic polar protic 18 polar protic polar aproticpolar protic polar aprotic 19 polar protic polar aprotic polar proticnonpolar protic 20 polar protic polar aprotic polar protic nonpolaraprotic 21 polar protic polar aprotic polar aprotic polar aprotic 22polar protic polar aprotic polar aprotic polar aprotic 23 polar proticpolar aprotic polar aprotic nonpolar protic 24 polar protic polaraprotic polar aprotic nonpolar aprotic 25 polar protic polar aproticnonpolar protic polar protic 26 polar protic polar aprotic nonpolarprotic polar aprotic 27 polar protic polar aprotic nonpolar proticnonpolar protic 28 polar protic polar aprotic nonpolar protic nonpolaraprotic 29 polar protic polar aprotic nonpolar aprotic polar protic 30polar protic polar aprotic nonpolar aprotic polar aprotic 31 polarprotic polar aprotic nonpolar aprotic nonpolar protic 32 polar proticpolar aprotic nonpolar aprotic nonpolar aprotic 33 polar protic nonpolarprotic polar protic polar protic 34 polar protic nonpolar protic polarprotic polar aprotic 35 polar protic nonpolar protic polar proticnonpolar protic 36 polar protic nonpolar protic polar protic nonpolaraprotic 37 polar protic nonpolar protic polar aprotic polar protic 38polar protic nonpolar protic polar aprotic polar aprotic 39 polar proticnonpolar protic polar aprotic nonpolar protic 40 polar protic nonpolarprotic polar aprotic nonpolar aprotic 41 polar protic nonpolar proticnonpolar protic polar protic 42 polar protic nonpolar protic nonpolarprotic polar aprotic 43 polar protic nonpolar protic nonpolar proticnonpolar protic 44 polar protic nonpolar protic nonpolar protic nonpolaraprotic 45 polar protic nonpolar protic nonpolar aprotic polar protic 46polar protic nonpolar protic nonpolar aprotic polar aprotic 47 polarprotic nonpolar protic nonpolar aprotic nonpolar protic 48 polar proticnonpolar protic nonpolar aprotic nonpolar aprotic 49 polar proticnonpolar aprotic polar protic polar protic 50 polar protic nonpolaraprotic polar protic polar aprotic 51 polar protic nonpolar aproticpolar protic nonpolar protic 52 polar protic nonpolar aprotic polarprotic nonpolar aprotic 53 polar protic nonpolar aprotic polar aproticpolar protic 54 polar protic nonpolar aprotic polar aprotic polaraprotic 55 polar protic nonpolar aprotic polar aprotic nonpolar protic56 polar protic nonpolar aprotic polar aprotic nonpolar aprotic 57 polarprotic nonpolar aprotic nonpolar protic polar protic 58 polar proticnonpolar aprotic nonpolar protic polar aprotic 59 polar protic nonpolaraprotic nonpolar protic nonpolar protic 60 polar protic nonpolar aproticnonpolar protic nonpolar aprotic 61 polar protic nonpolar aproticnonpolar aprotic polar protic 62 polar protic nonpolar aprotic nonpolaraprotic polar aprotic 63 polar protic nonpolar aprotic nonpolar aproticnonpolar protic 64 polar protic nonpolar aprotic nonpolar aproticnonpolar aprotic 65 polar aprotic polar protic polar protic polar protic66 polar aprotic polar protic polar protic polar aprotic 67 polaraprotic polar protic polar protic nonpolar protic 68 polar aprotic polarprotic polar protic nonpolar aprotic 69 polar aprotic polar protic polaraprotic polar protic 70 polar aprotic polar protic polar aprotic polaraprotic 71 polar aprotic polar protic polar aprotic nonpolar protic 72polar aprotic polar protic polar aprotic nonpolar aprotic 73 polaraprotic polar protic nonpolar protic polar protic 74 polar aprotic polarprotic nonpolar protic polar aprotic 75 polar aprotic polar proticnonpolar protic nonpolar protic 76 polar aprotic polar protic nonpolarprotic nonpolar aprotic 77 polar aprotic polar protic nonpolar aproticpolar protic 78 polar aprotic polar protic nonpolar aprotic polaraprotic 79 polar aprotic polar protic nonpolar aprotic nonpolar protic80 polar aprotic polar protic nonpolar aprotic nonpolar aprotic 81 polaraprotic polar aprotic polar protic polar protic 82 polar aprotic polaraprotic polar protic polar aprotic 83 polar aprotic polar aprotic polarprotic nonpolar protic 84 polar aprotic polar aprotic polar proticnonpolar aprotic 85 polar aprotic polar aprotic polar aprotic polaraprotic 86 polar aprotic polar aprotic polar aprotic polar aprotic 87polar aprotic polar aprotic polar aprotic nonpolar protic 88 polaraprotic polar aprotic polar aprotic nonpolar aprotic 89 polar aproticpolar aprotic nonpolar protic polar protic 90 polar aprotic polaraprotic nonpolar protic polar aprotic 91 polar aprotic polar aproticnonpolar protic nonpolar protic 92 polar aprotic polar aprotic nonpolarprotic nonpolar aprotic 93 polar aprotic polar aprotic nonpolar aproticpolar protic 94 polar aprotic polar aprotic nonpolar aprotic polaraprotic 95 polar aprotic polar aprotic nonpolar aprotic nonpolar protic96 polar aprotic polar aprotic nonpolar aprotic nonpolar aprotic 97polar aprotic nonpolar protic polar protic polar protic 98 polar aproticnonpolar protic polar protic polar aprotic 99 polar aprotic nonpolarprotic polar protic nonpolar protic 100 polar aprotic nonpolar proticpolar protic nonpolar aprotic 101 polar aprotic nonpolar protic polaraprotic polar protic 102 polar aprotic nonpolar protic polar aproticpolar aprotic 103 polar aprotic nonpolar protic polar aprotic nonpolarprotic 104 polar aprotic nonpolar protic polar aprotic nonpolar aprotic105 polar aprotic nonpolar protic nonpolar protic polar protic 106 polaraprotic nonpolar protic nonpolar protic polar aprotic 107 polar aproticnonpolar protic nonpolar protic nonpolar protic 108 polar aproticnonpolar protic nonpolar protic nonpolar aprotic 109 polar aproticnonpolar protic nonpolar aprotic polar protic 110 polar aprotic nonpolarprotic nonpolar aprotic polar aprotic 111 polar aprotic nonpolar proticnonpolar aprotic nonpolar protic 112 polar aprotic nonpolar proticnonpolar aprotic nonpolar aprotic 113 polar aprotic nonpolar aproticpolar protic polar protic 114 polar aprotic nonpolar aprotic polarprotic polar aprotic 115 polar aprotic nonpolar aprotic polar proticnonpolar protic 116 polar aprotic nonpolar aprotic polar protic nonpolaraprotic 117 polar aprotic nonpolar aprotic polar aprotic polar protic118 polar aprotic nonpolar aprotic polar aprotic polar aprotic 119 polaraprotic nonpolar aprotic polar aprotic nonpolar protic 120 polar aproticnonpolar aprotic polar aprotic nonpolar aprotic 121 polar aproticnonpolar aprotic nonpolar protic polar protic 122 polar aprotic nonpolaraprotic nonpolar protic polar aprotic 123 polar aprotic nonpolar aproticnonpolar protic nonpolar protic 124 polar aprotic nonpolar aproticnonpolar protic nonpolar aprotic 125 polar aprotic nonpolar aproticnonpolar aprotic polar protic 126 polar aprotic nonpolar aproticnonpolar aprotic polar aprotic 127 polar aprotic nonpolar aproticnonpolar aprotic nonpolar protic 128 polar aprotic nonpolar aproticnonpolar aprotic nonpolar aprotic 129 nonpolar protic polar protic polarprotic polar protic 130 nonpolar protic polar protic polar protic polaraprotic 131 nonpolar protic polar protic polar protic nonpolar protic132 nonpolar protic polar protic polar protic nonpolar aprotic 133nonpolar protic polar protic polar aprotic polar protic 134 nonpolarprotic polar protic polar aprotic polar aprotic 135 nonpolar proticpolar protic polar aprotic nonpolar protic 136 nonpolar protic polarprotic polar aprotic nonpolar aprotic 137 nonpolar protic polar proticnonpolar protic polar protic 138 nonpolar protic polar protic nonpolarprotic polar aprotic 139 nonpolar protic polar protic nonpolar proticnonpolar protic 140 nonpolar protic polar protic nonpolar proticnonpolar aprotic 141 nonpolar protic polar protic nonpolar aprotic polarprotic 142 nonpolar protic polar protic nonpolar aprotic polar aprotic143 nonpolar protic polar protic nonpolar aprotic nonpolar protic 144nonpolar protic polar protic nonpolar aprotic nonpolar aprotic 145nonpolar protic polar aprotic polar protic polar protic 146 nonpolarprotic polar aprotic polar protic polar aprotic 147 nonpolar proticpolar aprotic polar protic nonpolar protic 148 nonpolar protic polaraprotic polar protic nonpolar aprotic 149 nonpolar protic polar aproticpolar aprotic polar aprotic 150 nonpolar protic polar aprotic polaraprotic polar aprotic 151 nonpolar protic polar aprotic polar aproticnonpolar protic 152 nonpolar protic polar aprotic polar aprotic nonpolaraprotic 153 nonpolar protic polar aprotic nonpolar protic polar protic154 nonpolar protic polar aprotic nonpolar protic polar aprotic 155nonpolar protic polar aprotic nonpolar protic nonpolar protic 156nonpolar protic polar aprotic nonpolar protic nonpolar aprotic 157nonpolar protic polar aprotic nonpolar aprotic polar protic 158 nonpolarprotic polar aprotic nonpolar aprotic polar aprotic 159 nonpolar proticpolar aprotic nonpolar aprotic nonpolar protic 160 nonpolar protic polaraprotic nonpolar aprotic nonpolar aprotic 161 nonpolar protic nonpolarprotic polar protic polar protic 162 nonpolar protic nonpolar proticpolar protic polar aprotic 163 nonpolar protic nonpolar protic polarprotic nonpolar protic 164 nonpolar protic nonpolar protic polar proticnonpolar aprotic 165 nonpolar protic nonpolar protic polar aprotic polarprotic 166 nonpolar protic nonpolar protic polar aprotic polar aprotic167 nonpolar protic nonpolar protic polar aprotic nonpolar protic 168nonpolar protic nonpolar protic polar aprotic nonpolar aprotic 169nonpolar protic nonpolar protic nonpolar protic polar protic 170nonpolar protic nonpolar protic nonpolar protic polar aprotic 171nonpolar protic nonpolar protic nonpolar protic nonpolar protic 172nonpolar protic nonpolar protic nonpolar protic nonpolar aprotic 173nonpolar protic nonpolar protic nonpolar aprotic polar protic 174nonpolar protic nonpolar protic nonpolar aprotic polar aprotic 175nonpolar protic nonpolar protic nonpolar aprotic nonpolar protic 176nonpolar protic nonpolar protic nonpolar aprotic nonpolar aprotic 177nonpolar protic nonpolar aprotic polar protic polar protic 178 nonpolarprotic nonpolar aprotic polar protic polar aprotic 179 nonpolar proticnonpolar aprotic polar protic nonpolar protic 180 nonpolar proticnonpolar aprotic polar protic nonpolar aprotic 181 nonpolar proticnonpolar aprotic polar aprotic polar protic 182 nonpolar protic nonpolaraprotic polar aprotic polar aprotic 183 nonpolar protic nonpolar aproticpolar aprotic nonpolar protic 184 nonpolar protic nonpolar aprotic polaraprotic nonpolar aprotic 185 nonpolar protic nonpolar aprotic nonpolarprotic polar protic 186 nonpolar protic nonpolar aprotic nonpolar proticpolar aprotic 187 nonpolar protic nonpolar aprotic nonpolar proticnonpolar protic 188 nonpolar protic nonpolar aprotic nonpolar proticnonpolar aprotic 189 nonpolar protic nonpolar aprotic nonpolar aproticpolar protic 190 nonpolar protic nonpolar aprotic nonpolar aprotic polaraprotic 191 nonpolar protic nonpolar aprotic nonpolar aprotic nonpolarprotic 192 nonpolar protic nonpolar aprotic nonpolar aprotic nonpolaraprotic 193 nonpolar aprotic polar protic polar protic polar protic 194nonpolar aprotic polar protic polar protic polar aprotic 195 nonpolaraprotic polar protic polar protic nonpolar protic 196 nonpolar aproticpolar protic polar protic nonpolar aprotic 197 nonpolar aprotic polarprotic polar aprotic polar protic 198 nonpolar aprotic polar proticpolar aprotic polar aprotic 199 nonpolar aprotic polar protic polaraprotic nonpolar protic 200 nonpolar aprotic polar protic polar aproticnonpolar aprotic 201 nonpolar aprotic polar protic nonpolar protic polarprotic 202 nonpolar aprotic polar protic nonpolar protic polar aprotic203 nonpolar aprotic polar protic nonpolar protic nonpolar protic 204nonpolar aprotic polar protic nonpolar protic nonpolar aprotic 205nonpolar aprotic polar protic nonpolar aprotic polar protic 206 nonpolaraprotic polar protic nonpolar aprotic polar aprotic 207 nonpolar aproticpolar protic nonpolar aprotic nonpolar protic 208 nonpolar aprotic polarprotic nonpolar aprotic nonpolar aprotic 209 nonpolar aprotic polaraprotic polar protic polar protic 210 nonpolar aprotic polar aproticpolar protic polar aprotic 211 nonpolar aprotic polar aprotic polarprotic nonpolar protic 212 nonpolar aprotic polar aprotic polar proticnonpolar aprotic 213 nonpolar aprotic polar aprotic polar aprotic polaraprotic 214 nonpolar aprotic polar aprotic polar aprotic polar aprotic215 nonpolar aprotic polar aprotic polar aprotic nonpolar protic 216nonpolar aprotic polar aprotic polar aprotic nonpolar aprotic 217nonpolar aprotic polar aprotic nonpolar protic polar protic 218 nonpolaraprotic polar aprotic nonpolar protic polar aprotic 219 nonpolar aproticpolar aprotic nonpolar protic nonpolar protic 220 nonpolar aprotic polaraprotic nonpolar protic nonpolar aprotic 221 nonpolar aprotic polaraprotic nonpolar aprotic polar protic 222 nonpolar aprotic polar aproticnonpolar aprotic polar aprotic 223 nonpolar aprotic polar aproticnonpolar aprotic nonpolar protic 224 nonpolar aprotic polar aproticnonpolar aprotic nonpolar aprotic 225 nonpolar aprotic nonpolar proticpolar protic polar protic 226 nonpolar aprotic nonpolar protic polarprotic polar aprotic 227 nonpolar aprotic nonpolar protic polar proticnonpolar protic 228 nonpolar aprotic nonpolar protic polar proticnonpolar aprotic 229 nonpolar aprotic nonpolar protic polar aproticpolar protic 230 nonpolar aprotic nonpolar protic polar aprotic polaraprotic 231 nonpolar aprotic nonpolar protic polar aprotic nonpolarprotic 232 nonpolar aprotic nonpolar protic polar aprotic nonpolaraprotic 233 nonpolar aprotic nonpolar protic nonpolar protic polarprotic 234 nonpolar aprotic nonpolar protic nonpolar protic polaraprotic 235 nonpolar aprotic nonpolar protic nonpolar protic nonpolarprotic 236 nonpolar aprotic nonpolar protic nonpolar protic nonpolaraprotic 237 nonpolar aprotic nonpolar protic nonpolar aprotic polarprotic 238 nonpolar aprotic nonpolar protic nonpolar aprotic polaraprotic 239 nonpolar aprotic nonpolar protic nonpolar aprotic nonpolarprotic 240 nonpolar aprotic nonpolar protic nonpolar aprotic nonpolaraprotic 241 nonpolar aprotic nonpolar aprotic polar protic polar protic242 nonpolar aprotic nonpolar aprotic polar protic polar aprotic 243nonpolar aprotic nonpolar aprotic polar protic nonpolar protic 244nonpolar aprotic nonpolar aprotic polar protic nonpolar aprotic 245nonpolar aprotic nonpolar aprotic polar aprotic polar protic 246nonpolar aprotic nonpolar aprotic polar aprotic polar aprotic 247nonpolar aprotic nonpolar aprotic polar aprotic nonpolar protic 248nonpolar aprotic nonpolar aprotic polar aprotic nonpolar aprotic 249nonpolar aprotic nonpolar aprotic nonpolar protic polar protic 250nonpolar aprotic nonpolar aprotic nonpolar protic polar aprotic 251nonpolar aprotic nonpolar aprotic nonpolar protic nonpolar protic 252nonpolar aprotic nonpolar aprotic nonpolar protic nonpolar aprotic 253nonpolar aprotic nonpolar aprotic nonpolar aprotic polar protic 254nonpolar aprotic nonpolar aprotic nonpolar aprotic polar aprotic 255nonpolar aprotic nonpolar aprotic nonpolar aprotic nonpolar protic 256nonpolar aprotic nonpolar aprotic nonpolar aprotic nonpolar aprotic

Pressure

When the SFE is carried out two times, each FSFE can independently becarried out at a pressure of about: (i) 750-4,000 psi, (ii) 4,000-7,000psi, or (iii) 7,000-25,000 psi.

In specific embodiments, the SFE is carried out two times, wherein thefirst and second FSFEs are carried out at pressures illustrated in anyone of 1-9 below. When the first and second FSFEs are carried out at thesame pressure range, those FSFEs will typically be carried out at adifferent temperature and/or solvent system having a differentcombination of polarity and proticity (e.g., carried out at the samepressure range, the first FSFE includes a polar aprotic solvent systemand the second FSFE includes a nonpolar protic solvent system).

First FSFE Second FSFE No. pressure pressure 1 750-4,000 psi 750-4,000psi 2 750-4,000 psi 4,000-7,000 psi 3 750-4,000 psi 7,000-25,000 psi 44,000-7,000 psi 750-4,000 psi 5 4,000-7,000 psi 4,000-7,000 psi 64,000-7,000 psi 7,000-25,000 psi 7 7,000-25,000 psi 750-4,000 psi 87,000-25,000 psi 4,000-7,000 psi 9 7,000-25,000 psi 7,000-25,000 psi

When the SFE is carried out three times, each FSFE can independently becarried out at a pressure of about: (i) 750-4,000 psi, (ii) 4,000-7,000psi, or (iii) 7,000-25,000 psi.

In specific embodiments, the SFE is carried out three times, wherein thefirst, second and third FSFEs are carried out at pressures illustratedin any one of 1-27 below. When any one or more of the first, second andthird FSFEs are carried out at the same pressure range, those FSFEs willtypically be carried out at a different temperature and/or solventsystem having a different combination of polarity and proticity (e.g.,carried out at the same pressure range, the second FSFE includes a polaraprotic solvent system and the third FSFE includes a nonpolar proticsolvent system).

First FSFE Second FSFE Third FSFE No. pressure pressure pressure 1750-4,000 psi 750-4,000 psi 750-4,000 psi 2 750-4,000 psi 750-4,000 psi4,000-7,000 psi 3 750-4,000 psi 750-4,000 psi 7,000-25,000 psi 4750-4,000 psi 4,000-7,000 psi 750-4,000 psi 5 750-4,000 psi 4,000-7,000psi 4,000-7,000 psi 6 750-4,000 psi 4,000-7,000 psi 7,000-25,000 psi 7750-4,000 psi 7,000-25,000 psi 750-4,000 psi 8 750-4,000 psi7,000-25,000 psi 4,000-7,000 psi 9 750-4,000 psi 7,000-25,000 psi7,000-25,000 psi 10 4,000-7,000 psi 750-4,000 psi 750-4,000 psi 114,000-7,000 psi 750-4,000 psi 4,000-7,000 psi 12 4,000-7,000 psi750-4,000 psi 7,000-25,000 psi 13 4,000-7,000 psi 4,000-7,000 psi750-4,000 psi 14 4,000-7,000 psi 4,000-7,000 psi 4,000-7,000 psi 154,000-7,000 psi 4,000-7,000 psi 7,000-25,000 psi 16 4,000-7,000 psi7,000-25,000 psi 750-4,000 psi 17 4,000-7,000 psi 7,000-25,000 psi4,000-7,000 psi 18 4,000-7,000 psi 7,000-25,000 psi 7,000-25,000 psi 197,000-25,000 psi 750-4,000 psi 750-4,000 psi 20 7,000-25,000 psi750-4,000 psi 4,000-7,000 psi 21 7,000-25,000 psi 750-4,000 psi7,000-25,000 psi 22 7,000-25,000 psi 4,000-7,000 psi 750-4,000 psi 237,000-25,000 psi 4,000-7,000 psi 4,000-7,000 psi 24 7,000-25,000 psi4,000-7,000 psi 7,000-25,000 psi 25 7,000-25,000 psi 7,000-25,000 psi750-4,000 psi 26 7,000-25,000 psi 7,000-25,000 psi 4,000-7,000 psi 277,000-25,000 psi 7,000-25,000 psi 7,000-25,000 psi

When the SFE is carried out four times, each FSFE can independently becarried out at a pressure of about: (i) 750-4,000 psi, (ii) 4,000-7,000psi, or (iii) 7,000-25,000 psi.

In specific embodiments, the SFE is carried out four times, wherein thefirst, second, third and fourth FSFEs are carried out at pressuresillustrated in any one of 1-81 below. When any one or more of the first,second, third and fourth FSFEs are carried out at the same pressurerange, those FSFEs will typically be carried out at a differenttemperature and/or solvent system having a different combination ofpolarity and proticity (e.g., carried out at the same pressure range,the third FSFE includes a polar aprotic solvent system and the fourthFSFE includes a nonpolar protic solvent system).

First FSFE Second FSFE Third FSFE Fourth FSFE No. pressure pressurepressure pressure 1 750-4,000 psi 750-4,000 psi 750-4,000 psi 750-4,000psi 2 750-4,000 psi 750-4,000 psi 750-4,000 psi 4,000-7,000 psi 3750-4,000 psi 750-4,000 psi 750-4,000 psi 7,000-25,000 psi 4 750-4,000psi 750-4,000 psi 4,000-7,000 psi 750-4,000 psi 5 750-4,000 psi750-4,000 psi 4,000-7,000 psi 4,000-7,000 psi 6 750-4,000 psi 750-4,000psi 4,000-7,000 psi 7,000-25,000 psi 7 750-4,000 psi 750-4,000 psi7,000-25,000 psi 750-4,000 psi 8 750-4,000 psi 750-4,000 psi7,000-25,000 psi 4,000-7,000 psi 9 750-4,000 psi 750-4,000 psi7,000-25,000 psi 7,000-25,000 psi 10 750-4,000 psi 4,000-7,000 psi750-4,000 psi 750-4,000 psi 11 750-4,000 psi 4,000-7,000 psi 750-4,000psi 4,000-7,000 psi 12 750-4,000 psi 4,000-7,000 psi 750-4,000 psi7,000-25,000 psi 13 750-4,000 psi 4,000-7,000 psi 4,000-7,000 psi750-4,000 psi 14 750-4,000 psi 4,000-7,000 psi 4,000-7,000 psi4,000-7,000 psi 15 750-4,000 psi 4,000-7,000 psi 4,000-7,000 psi7,000-25,000 psi 16 750-4,000 psi 4,000-7,000 psi 7,000-25,000 psi750-4,000 psi 17 750-4,000 psi 4,000-7,000 psi 7,000-25,000 psi4,000-7,000 psi 18 750-4,000 psi 4,000-7,000 psi 7,000-25,000 psi7,000-25,000 psi 19 750-4,000 psi 7,000-25,000 psi 750-4,000 psi750-4,000 psi 20 750-4,000 psi 7,000-25,000 psi 750-4,000 psi4,000-7,000 psi 21 750-4,000 psi 7,000-25,000 psi 750-4,000 psi7,000-25,000 psi 22 750-4,000 psi 7,000-25,000 psi 4,000-7,000 psi750-4,000 psi 23 750-4,000 psi 7,000-25,000 psi 4,000-7,000 psi4,000-7,000 psi 24 750-4,000 psi 7,000-25,000 psi 4,000-7,000 psi7,000-25,000 psi 25 750-4,000 psi 7,000-25,000 psi 7,000-25,000 psi750-4,000 psi 26 750-4,000 psi 7,000-25,000 psi 7,000-25,000 psi4,000-7,000 psi 27 750-4,000 psi 7,000-25,000 psi 7,000-25,000 psi7,000-25,000 psi 28 4,000-7,000 psi 750-4,000 psi 750-4,000 psi750-4,000 psi 29 4,000-7,000 psi 750-4,000 psi 750-4,000 psi 4,000-7,000psi 30 4,000-7,000 psi 750-4,000 psi 750-4,000 psi 7,000-25,000 psi 314,000-7,000 psi 750-4,000 psi 4,000-7,000 psi 750-4,000 psi 324,000-7,000 psi 750-4,000 psi 4,000-7,000 psi 4,000-7,000 psi 334,000-7,000 psi 750-4,000 psi 4,000-7,000 psi 7,000-25,000 psi 344,000-7,000 psi 750-4,000 psi 7,000-25,000 psi 750-4,000 psi 354,000-7,000 psi 750-4,000 psi 7,000-25,000 psi 4,000-7,000 psi 364,000-7,000 psi 750-4,000 psi 7,000-25,000 psi 7,000-25,000 psi 374,000-7,000 psi 4,000-7,000 psi 750-4,000 psi 750-4,000 psi 384,000-7,000 psi 4,000-7,000 psi 750-4,000 psi 4,000-7,000 psi 394,000-7,000 psi 4,000-7,000 psi 750-4,000 psi 7,000-25,000 psi 404,000-7,000 psi 4,000-7,000 psi 4,000-7,000 psi 750-4,000 psi 414,000-7,000 psi 4,000-7,000 psi 4,000-7,000 psi 4,000-7,000 psi 424,000-7,000 psi 4,000-7,000 psi 4,000-7,000 psi 7,000-25,000 psi 434,000-7,000 psi 4,000-7,000 psi 7,000-25,000 psi 750-4,000 psi 444,000-7,000 psi 4,000-7,000 psi 7,000-25,000 psi 4,000-7,000 psi 454,000-7,000 psi 4,000-7,000 psi 7,000-25,000 psi 7,000-25,000 psi 464,000-7,000 psi 7,000-25,000 psi 750-4,000 psi 750-4,000 psi 474,000-7,000 psi 7,000-25,000 psi 750-4,000 psi 4,000-7,000 psi 484,000-7,000 psi 7,000-25,000 psi 750-4,000 psi 7,000-25,000 psi 494,000-7,000 psi 7,000-25,000 psi 4,000-7,000 psi 750-4,000 psi 504,000-7,000 psi 7,000-25,000 psi 4,000-7,000 psi 4,000-7,000 psi 514,000-7,000 psi 7,000-25,000 psi 4,000-7,000 psi 7,000-25,000 psi 524,000-7,000 psi 7,000-25,000 psi 7,000-25,000 psi 750-4,000 psi 534,000-7,000 psi 7,000-25,000 psi 7,000-25,000 psi 4,000-7,000 psi 544,000-7,000 psi 7,000-25,000 psi 7,000-25,000 psi 7,000-25,000 psi 557,000-25,000 psi 750-4,000 psi 750-4,000 psi 750-4,000 psi 567,000-25,000 psi 750-4,000 psi 750-4,000 psi 4,000-7,000 psi 577,000-25,000 psi 750-4,000 psi 750-4,000 psi 7,000-25,000 psi 587,000-25,000 psi 750-4,000 psi 4,000-7,000 psi 750-4,000 psi 597,000-25,000 psi 750-4,000 psi 4,000-7,000 psi 4,000-7,000 psi 607,000-25,000 psi 750-4,000 psi 4,000-7,000 psi 7,000-25,000 psi 617,000-25,000 psi 750-4,000 psi 7,000-25,000 psi 750-4,000 psi 627,000-25,000 psi 750-4,000 psi 7,000-25,000 psi 4,000-7,000 psi 637,000-25,000 psi 750-4,000 psi 7,000-25,000 psi 7,000-25,000 psi 647,000-25,000 psi 4,000-7,000 psi 750-4,000 psi 750-4,000 psi 657,000-25,000 psi 4,000-7,000 psi 750-4,000 psi 4,000-7,000 psi 667,000-25,000 psi 4,000-7,000 psi 750-4,000 psi 7,000-25,000 psi 677,000-25,000 psi 4,000-7,000 psi 4,000-7,000 psi 750-4,000 psi 687,000-25,000 psi 4,000-7,000 psi 4,000-7,000 psi 4,000-7,000 psi 697,000-25,000 psi 4,000-7,000 psi 4,000-7,000 psi 7,000-25,000 psi 707,000-25,000 psi 4,000-7,000 psi 7,000-25,000 psi 750-4,000 psi 717,000-25,000 psi 4,000-7,000 psi 7,000-25,000 psi 4,000-7,000 psi 727,000-25,000 psi 4,000-7,000 psi 7,000-25,000 psi 7,000-25,000 psi 737,000-25,000 psi 7,000-25,000 psi 750-4,000 psi 750-4,000 psi 747,000-25,000 psi 7,000-25,000 psi 750-4,000 psi 4,000-7,000 psi 757,000-25,000 psi 7,000-25,000 psi 750-4,000 psi 7,000-25,000 psi 767,000-25,000 psi 7,000-25,000 psi 4,000-7,000 psi 750-4,000 psi 777,000-25,000 psi 7,000-25,000 psi 4,000-7,000 psi 4,000-7,000 psi 787,000-25,000 psi 7,000-25,000 psi 4,000-7,000 psi 7,000-25,000 psi 797,000-25,000 psi 7,000-25,000 psi 7,000-25,000 psi 750-4,000 psi 807,000-25,000 psi 7,000-25,000 psi 7,000-25,000 psi 4,000-7,000 psi 817,000-25,000 psi 7,000-25,000 psi 7,000-25,000 psi 7,000-25,000 psi

Temperature

When the SFE is carried out two times, each FSFE can independently becarried out at a temperature of about: (i) −15-70° C., (ii) 70-100° C.,or (iii) 100-200° C.

In specific embodiments, the SFE is carried out two times, wherein thefirst and second FSFEs are carried out at temperatures illustrated inany one of 1-9 below. When the first and second FSFEs are carried out atthe same temperature range, those FSFEs will typically be carried out ata different pressure and/or solvent system having a differentcombination of polarity and proticity (e.g., carried out at the samepressure range, the first FSFE includes a polar aprotic solvent systemand the second FSFE includes a nonpolar protic solvent system).

First FSFE Second FSFE No. temperature temperature 1 −15-70° C. −15-70°C. 2 −15-70° C. 70-100° C. 3 −15-70° C. 100-200° C. 4 70-100° C. −15-70°C. 5 70-100° C. 70-100° C. 6 70-100° C. 100-200° C. 7 100-200° C.−15-70° C. 8 100-200° C. 70-100° C. 9 100-200° C. 100-200° C.

When the SFE is carried out three times, each FSFE can independently becarried out at a temperature of about: (i) −15-70° C., (ii) 70-100° C.,or (iii) 100-200° C.

In specific embodiments, the SFE is carried out three times, wherein thefirst, second and third FSFEs are carried out at temperaturesillustrated in any one of 1-27 below. When the first, second and thirdFSFEs are carried out at the same temperature range, those FSFEs willtypically be carried out at a different pressure and/or solvent systemhaving a different combination of polarity and proticity (e.g., carriedout at the same pressure range, the second FSFE includes a polar aproticsolvent system and the third FSFE includes a nonpolar protic solventsystem).

First FSFE Second FSFE Third FSFE No. temperature temperaturetemperature 1 −15-70° C. −15-70° C. −15-70° C. 2 −15-70° C. −15-70° C.70-100° C. 3 −15-70° C. −15-70° C. 100-200° C. 4 −15-70° C. 70-100° C.−15-70° C. 5 −15-70° C. 70-100° C. 70-100° C. 6 −15-70° C. 70-100° C.100-200° C. 7 −15-70° C. 100-200° C. −15-70° C. 8 −15-70° C. 100-200° C.70-100° C. 9 −15-70° C. 100-200° C. 100-200° C. 10 70-100° C. −15-70° C.−15-70° C. 11 70-100° C. −15-70° C. 70-100° C. 12 70-100° C. −15-70° C.100-200° C. 13 70-100° C. 70-100° C. −15-70° C. 14 70-100° C. 70-100° C.70-100° C. 15 70-100° C. 70-100° C. 100-200° C. 16 70-100° C. 100-200°C. −15-70° C. 17 70-100° C. 100-200° C. 70-100° C. 18 70-100° C.100-200° C. 100-200° C. 19 100-200° C. −15-70° C. −15-70° C. 20 100-200°C. −15-70° C. 70-100° C. 21 100-200° C. −15-70° C. 100-200° C. 22100-200° C. 70-100° C. −15-70° C. 23 100-200° C. 70-100° C. 70-100° C.24 100-200° C. 70-100° C. 100-200° C. 25 100-200° C. 100-200° C. −15-70°C. 26 100-200° C. 100-200° C. 70-100° C. 27 100-200° C. 100-200° C.100-200° C.

When the SFE is carried out four times, each FSFE can independently becarried out at a temperature of about: (i) −15-70° C., (ii) 70-100° C.,or (iii) 100-200° C.

In specific embodiments, the SFE is carried out four times, wherein thefirst, second, third and fourth FSFEs are carried out at temperaturesillustrated in any one of 1-81 below. When the first, second, third andfourth FSFEs are carried out at the same temperature range, those FSFEswill typically be carried out at a different pressure and/or solventsystem having a different combination of polarity and proticity (e.g.,carried out at the same pressure range, the third FSFE includes a polaraprotic solvent system and the fourth FSFE includes a nonpolar proticsolvent system).

First FSFE Second FSFE Third FSFE Fourth FSFE No. temperaturetemperature temperature temperature 1 −15-70° C. −15-70° C. −15-70° C.−15-70° C. 2 −15-70° C. −15-70° C. −15-70° C. 70-100° C. 3 −15-70° C.−15-70° C. −15-70° C. 100-200° C. 4 −15-70° C. −15-70° C. 70-100° C.−15-70° C. 5 −15-70° C. −15-70° C. 70-100° C. 70-100° C. 6 −15-70° C.−15-70° C. 70-100° C. 100-200° C. 7 −15-70° C. −15-70° C. 100-200° C.−15-70° C. 8 −15-70° C. −15-70° C. 100-200° C. 70-100° C. 9 −15-70° C.−15-70° C. 100-200° C. 100-200° C. 10 −15-70° C. 70-100° C. −15-70° C.−15-70° C. 11 −15-70° C. 70-100° C. −15-70° C. 70-100° C. 12 −15-70° C.70-100° C. −15-70° C. 100-200° C. 13 −15-70° C. 70-100° C. 70-100° C.−15-70° C. 14 −15-70° C. 70-100° C. 70-100° C. 70-100° C. 15 −15-70° C.70-100° C. 70-100° C. 100-200° C. 16 −15-70° C. 70-100° C. 100-200° C.−15-70° C. 17 −15-70° C. 70-100° C. 100-200° C. 70-100° C. 18 −15-70° C.70-100° C. 100-200° C. 100-200° C. 19 −15-70° C. 100-200° C. −15-70° C.−15-70° C. 20 −15-70° C. 100-200° C. −15-70° C. 70-100° C. 21 −15-70° C.100-200° C. −15-70° C. 100-200° C. 22 −15-70° C. 100-200° C. 70-100° C.−15-70° C. 23 −15-70° C. 100-200° C. 70-100° C. 70-100° C. 24 −15-70° C.100-200° C. 70-100° C. 100-200° C. 25 −15-70° C. 100-200° C. 100-200° C.−15-70° C. 26 −15-70° C. 100-200° C. 100-200° C. 70-100° C. 27 −15-70°C. 100-200° C. 100-200° C. 100-200° C. 28 70-100° C. −15-70° C. −15-70°C. −15-70° C. 29 70-100° C. −15-70° C. −15-70° C. 70-100° C. 30 70-100°C. −15-70° C. −15-70° C. 100-200° C. 31 70-100° C. −15-70° C. 70-100° C.−15-70° C. 32 70-100° C. −15-70° C. 70-100° C. 70-100° C. 33 70-100° C.−15-70° C. 70-100° C. 100-200° C. 34 70-100° C. −15-70° C. 100-200° C.−15-70° C. 35 70-100° C. −15-70° C. 100-200° C. 70-100° C. 36 70-100° C.−15-70° C. 100-200° C. 100-200° C. 37 70-100° C. 70-100° C. −15-70° C.−15-70° C. 38 70-100° C. 70-100° C. −15-70° C. 70-100° C. 39 70-100° C.70-100° C. −15-70° C. 100-200° C. 40 70-100° C. 70-100° C. 70-100° C.−15-70° C. 41 70-100° C. 70-100° C. 70-100° C. 70-100° C. 42 70-100° C.70-100° C. 70-100° C. 100-200° C. 43 70-100° C. 70-100° C. 100-200° C.−15-70° C. 44 70-100° C. 70-100° C. 100-200° C. 70-100° C. 45 70-100° C.70-100° C. 100-200° C. 100-200° C. 46 70-100° C. 100-200° C. −15-70° C.−15-70° C. 47 70-100° C. 100-200° C. −15-70° C. 70-100° C. 48 70-100° C.100-200° C. −15-70° C. 100-200° C. 49 70-100° C. 100-200° C. 70-100° C.−15-70° C. 50 70-100° C. 100-200° C. 70-100° C. 70-100° C. 51 70-100° C.100-200° C. 70-100° C. 100-200° C. 52 70-100° C. 100-200° C. 100-200° C.−15-70° C. 53 70-100° C. 100-200° C. 100-200° C. 70-100° C. 54 70-100°C. 100-200° C. 100-200° C. 100-200° C. 55 100-200° C. −15-70° C. −15-70°C. −15-70° C. 56 100-200° C. −15-70° C. −15-70° C. 70-100° C. 57100-200° C. −15-70° C. −15-70° C. 100-200° C. 58 100-200° C. −15-70° C.70-100° C. −15-70° C. 59 100-200° C. −15-70° C. 70-100° C. 70-100° C. 60100-200° C. −15-70° C. 70-100° C. 100-200° C. 61 100-200° C. −15-70° C.100-200° C. −15-70° C. 62 100-200° C. −15-70° C. 100-200° C. 70-100° C.63 100-200° C. −15-70° C. 100-200° C. 100-200° C. 64 100-200° C. 70-100°C. −15-70° C. −15-70° C. 65 100-200° C. 70-100° C. −15-70° C. 70-100° C.66 100-200° C. 70-100° C. −15-70° C. 100-200° C. 67 100-200° C. 70-100°C. 70-100° C. −15-70° C. 68 100-200° C. 70-100° C. 70-100° C. 70-100° C.69 100-200° C. 70-100° C. 70-100° C. 100-200° C. 70 100-200° C. 70-100°C. 100-200° C. −15-70° C. 71 100-200° C. 70-100° C. 100-200° C. 70-100°C. 72 100-200° C. 70-100° C. 100-200° C. 100-200° C. 73 100-200° C.100-200° C. −15-70° C. −15-70° C. 74 100-200° C. 100-200° C. −15-70° C.70-100° C. 75 100-200° C. 100-200° C. −15-70° C. 100-200° C. 76 100-200°C. 100-200° C. 70-100° C. −15-70° C. 77 100-200° C. 100-200° C. 70-100°C. 70-100° C. 78 100-200° C. 100-200° C. 70-100° C. 100-200° C. 79100-200° C. 100-200° C. 100-200° C. −15-70° C. 80 100-200° C. 100-200°C. 100-200° C. 70-100° C. 81 100-200° C. 100-200° C. 100-200° C.100-200° C.

Prophetic Examples

The prophetic examples 1-8 below can be carried out employingtechniques, materials, and equipment known to those reasonably skilledin the art.

General Description:

1 kg of freshly harvested Cannabis sativa is placed in a SFE extractionvessel (25 L). 10 L of solvent system is introduced into the SFEextraction vessel. The solvent system is initially cooled to maintainliquid conditions, then heated after pressurization. The desiredtemperature and pressure is achieved. The SFE extraction vessel isshaken to facilitate extraction. After the requisite period of time, thetemperature and pressure are lowered to ambient conditions. The processis optionally repeated, one or more times. The spent plant material isseparated from the extract, wherein the extract is optionally furtherprocessed to provide a concentrate.

Number of SFE Solvent SFE SFE SFE Cannabis extract SFEs/FSFEs SystemPressure Temperature Time (expected) Example 1: 1 Polar protic 3,500 psi60° C. 60 min cannabinolic acid (CBNA); (CO₂ andΔ(9)-tetrahydrocannabinolic acid (Δ(9)-THCA); EtOH)Δ(9)-tetrahydrocannabidiolic acid (Δ(9)- CBDA);Δ(8)-tetrahydrocannabinolic acid (Δ(8)-THCA);Δ(8)-tetrahydrocannabidiolic acid (Δ(8)-CBDA);Δ(9)-tetrahydrocannabivarin (Δ(9)-THV); cannabigerolic acid (CBGA);cannabichromenic acid (CBCA); and cannabicyclolic acid (CBLA) Example 2:1 Nonpolar 7,500 psi 90° C. 60 min Δ(9)-tetrahydrocannabinol aprotic(CO₂ (Δ(9)-THC); and pentanes) cannabinol (CBN); Δ(9)-cannabidiol(Δ(9)-CBD); Δ(8)-tetrahydrocannabinol (Δ(8)-THC);Δ(8)-tetrahydrocannabidiol Δ(8)-CBD); cannabigerol (CBG);cannabichromene (CBC); cannabicyclol (CBL); β-caryophyllene epoxide;mentha-1,8(9)-dien-5-ol; pulegone; limonene oxide; α-terpinene;terpinen-4-ol; carvacrol; carvone; 1,8-cineole; p-cymene; fenchone;pulegone-1,2epoxide; β-myrcene; cannaflavin A; and cannaflavin B Example3: 2 i. Polar protic i. 1,500 psi i. 80° C. i. 24 min i. cannabinolicacid (CBNA); (CO₂ and ii. 7,500 psi ii. 70° C. ii. 26 minΔ(9)-tetrahydrocannabinolic acid (Δ(9)-THCA); EtOH)Δ(9)-tetrahydrocannabidiolic acid (Δ(9)- ii. Nonpolar CBDA); aprotic(CO₂ Δ(8)-tetrahydrocannabinolic acid (Δ(8)-THCA); and pentanes)Δ(8)-tetrahydrocannabidiolic acid (Δ(8)-CBDA);Δ(9)-tetrahydrocannabivarin (Δ(9)-THV); cannabigerolic acid (CBGA);cannabichromenic acid (CBCA); and cannabicyclolic acid (CBLA) ii.Δ(9)-tetrahydrocannabinol (Δ(9)-THC); cannabinol (CBN); Δ(9)-cannabidiol(Δ(9)-CBD); Δ(8)-tetrahydrocannabinol (Δ(8)-THC);Δ(8)-tetrahydrocannabidiol (Δ(8)-CBD); cannabigerol (CBG);cannabichromene (CBC); cannabicyclol (CBL); β-caryophyllene epoxide;mentha-1,8(9)-dien-5-ol; pulegone; limonene oxide; α-terpinene;terpinen-4-ol; carvacrol; carvone; 1,8-cineole; p-cymene; fenchone;pulegone-1,2epoxide; β-myrcene; cannaflavin A; and cannaflavin B Example4: 2 i. Nonpolar i. 1,500 psi i. 90° C. i. 38 min i.Δ(9)-tetrahydrocannabinol aprotic (CO² ii. 4,500 psi ii. 70° C. ii. 34min (Δ(9)-THC); and pentanes) cannabinol (CBN); ii. Polar proticΔ(9)-cannabidiol (Δ(9)-CBD); (CO₂ and Δ(8)-tetrahydrocannabinol EtOH)(Δ(8)-THC); Δ(8)-tetrahydrocannabidiol (Δ(8)-CBD); cannabigerol (CBG);cannabichromene (CBC); cannabicyclol (CBL); β-caryophyllene epoxide;mentha-1,8(9)-dien-5-ol; pulegone; limonene oxide; α-terpinene;terpinen-4-ol; carvacrol; carvone; 1,8-cineole; p-cymene; fenchone;pulegone-1,2epoxide; β-myrcene; cannaflavin A; and cannaflavin B ii.cannabinolic acid (CBNA); Δ(9)-tetrahydrocannabinolic acid (Δ(9)-THCA);Δ(9)-tetrahydrocannabidiolic acid (Δ(9)- CBDA);Δ(8)-tetrahydrocannabinolic acid (Δ(8)-THCA);Δ(8)-tetrahydrocannabidiolic acid (Δ(8)-CBDA);Δ(9)-tetrahydrocannabivarin (Δ(9)-THV); cannabigerolic acid (CBGA);cannabichromenic acid (CBCA); and cannabicyclolic acid (CBLA) Example 5:2 i. Polar protic i. 4,000 psi i. 80° C. i. 26 min i. cannabinolic acid(CBNA); (CO₂ and ii. 4,000 psi ii. 60° C. ii. 28 minΔ(9)-tetrahydrocannabinolic acid (Δ(9)-THCA); EtOH)Δ(9)-tetrahydrocannabidiolic acid (Δ(9)- ii. NonpolarCBDA);Δ(8)-tetrahydrocannabinolic acid (Δ(8)-THCA); aprotic (CO₂Δ(8)-tetrahydrocannabidiolic and pentanes) acid (Δ(8)-CBDA);Δ(9)-tetrahydrocannabivarin (Δ(9)-THV); cannabigerolic acid (CBGA);cannabichromenic acid (CBCA); and cannabicyclolic acid (CBLA) ii.Δ(9)-tetrahydrocannabinol (Δ(9)-THC); cannabinol (CBN); Δ(9)-cannabidiol(Δ(9)-CBD); Δ(8)-tetrahydrocannabinol (Δ(8)-THC);Δ(8)-tetrahydrocannabidiol (Δ(8)-CBD); cannabigerol (CBG);cannabichromene (CBC); cannabicyclol (CBL); β-caryophyllene epoxide;mentha-1,8(9)-dien-5-ol; pulegone; limonene oxide; α-terpinene;terpinen-4-ol; carvacrol; carvone; 1,8-cineole; p-cymene; fenchone;pulegone-1,2epoxide; β-myrcene; cannaflavin A; and cannaflavin B Example6: 2 i. Nonpolar i. 5,000 psi i. 110° C. i. 37 min i.Δ(9)-tetrahydrocannabinol aprotic (CO₂ ii. 5,000 psi ii. 80° C. ii. 39min (Δ(9)-THC); and pentanes) cannabinol (CBN); ii. Polar proticΔ(9)-cannabidiol (Δ(9)-CBD); (CO₂ and Δ(8)-tetrahydrocannabinol EtOH)(Δ(8)-THC); Δ(8)-tetrahydrocannabidiol(Δ(8)-CBD); cannabigerol (CBG);cannabichromene (CBC); cannabicyclol (CBL); β-caryophyllene epoxide;mentha-1,8(9)-dien-5-ol; pulegone; limonene oxide; α-terpinene;terpinen-4-ol; carvacrol; carvone; 1,8-cineole; p-cymene; fenchone;pulegone-1,2epoxide; β-myrcene; cannaflavin A; and cannaflavin B ii.cannabinolic acid (CBNA); Δ(9)-tetrahydrocannabinolic acid (Δ(9)-THCA);Δ(9)-tetrahydrocannabidiolic acid (Δ(9)- CBDA);Δ(8)-tetrahydrocannabinolic acid (Δ(8)-THCA);Δ(8)-tetrahydrocannabidiolic acid (Δ(8)-CBDA);Δ(9)-tetrahydrocannabivarin (Δ(9)-THV); cannabigerolic acid (CBGA);cannabichromenic acid (CBCA); and cannabicyclolic acid (CBLA) Example 7:2 i. Polar protic i. 1,500 psi i. 110° C. i. 34 min i. cannabinolic acid(CBNA); (CO₂ and ii. 7,500 psi ii. 110° C. ii. 37 minΔ(9)-tetrahydrocannabinolic acid (Δ(9)-THCA); EtOH)Δ(9)-tetrahydrocannabidiolic acid (Δ(9)- ii. Nonpolar CBDA); aprotic(CO₂ Δ(8)-tetrahydrocannabinolic acid (Δ(8)-THCA); and pentanes)Δ(8)-tetrahydrocannabidiolic acid (Δ(8)-CBDA);Δ(9)-tetrahydrocannabivarin (Δ(9)-THV); cannabigerolic acid (CBGA);cannabichromenic acid (CBCA); and cannabicyclolic acid (CBLA) ii.Δ(9)-tetrahydrocannabinol (Δ(9)-THC); cannabinol (CBN); Δ(9)-cannabidiol(Δ(9)-CBD); Δ(8)-tetrahydrocannabinol (Δ(8)-THC);Δ(8)-tetrahydrocannabidiol (Δ(8)-CBD); cannabigerol (CBG);cannabichromene (CBC); cannabicyclol (CBL); β-caryophyllene epoxide;mentha-1,8(9)-dien-5-ol; pulegone; limonene oxide; α-terpinene;terpinen-4-ol; carvacrol; carvone; 1,8-cineole; p-cymene; fenchone;pulegone-1,2epoxide; β-myrcene; cannaflavin A; and cannaflavin B Example8: 2 i. Nonpolar i. 1,500 psi i. 120° C. i. 35 min i.Δ(9)-tetrahydrocannabinol aprotic (CO₂ ii. 4,500 psi ii. 120° C. ii. 38min (Δ(9)-THC); and pentanes) cannabinol (CBN); ii. Polar proticΔ(9)-cannabidiol (Δ(9)-CBD); (CO₂ and Δ(8)-tetrahydrocannabinol EtOH)(Δ(8)-THC); Δ(8)-tetrahydrocannabidiol (Δ(8)-CBD); cannabigerol (CBG);cannabichromene (CBC); cannabicyclol (CBL); β-caryophyllene epoxide;mentha-1,8(9)-dien-5-ol; pulegone; limonene oxide; α-terpinene;terpinen-4-ol; carvacrol; carvone; 1,8-cineole; p-cymene; fenchone;pulegone-1,2epoxide; β-myrcene; cannaflavin A; and cannaflavin B ii.cannabinolic acid (CBNA); Δ(9)-tetrahydrocannabinolic acid (Δ(9)-THCA);Δ(9)-tetrahydrocannabidiolic acid (Δ(9)- CBDA);Δ(8)-tetrahydrocannabinolic acid (Δ(8)-THCA);Δ(8)-tetrahydrocannabidiolic acid (Δ(8)-CBDA);Δ(9)-tetrahydrocannabivarin (Δ(9)-THV); cannabigerolic acid (CBGA);cannabichromenic acid (CBCA); and cannabicyclolic acid (CBLA)

Embodiments

Specific enumerated embodiments [1] to [146] provided below are forillustration purposes only, and do not otherwise limit the scope of thedisclosed subject matter, as defined by the embodiments. Theseenumerated embodiments encompass all combinations, sub-combinations, andmultiply referenced (e.g., multiply dependent) combinations describedtherein.

[1.] A process for obtaining an extract of Cannabis, the processincluding:

(a) contacting Cannabis with a supercritical fluid solvent system at apressure between about 750 psi and 25,000 psi, and at a temperaturebetween about −15° C. and 200° C., to provide an extract of Cannabis;and

(b) optionally removing the supercritical fluid solvent system from theextract of Cannabis to provide a concentrate of Cannabis.

[2.] A process for obtaining an extract of Cannabis, the processincluding:

(a) contacting Cannabis plant material with a supercritical fluidsolvent system at a pressure between about 750 psi and 25,000 psi, andat a temperature between about −15° C. and 200° C., to provide anextract of Cannabis and an extracted Cannabis;

(b) removing the supercritical fluid solvent system from the extract ofCannabis to provide a concentrate of Cannabis;

(c) contacting the extracted Cannabis plant material with a secondsupercritical fluid solvent system at a pressure between about 750 psiand 25,000 psi, and at a temperature between about −15° C. and 200° C.,to provide a second extract of Cannabis and a second extracted Cannabisplant material; and

(d) optionally removing the second supercritical fluid solvent systemfrom the second extract of Cannabis to provide a second concentrate ofCannabis.

[3.] A process for obtaining an extract of Cannabis, the processincluding:

(a) contacting Cannabis with a supercritical fluid solvent system at apressure between about 750 psi and 25,000 psi, and at a temperaturebetween about −15° C. and 200° C., to provide an extract of Cannabis andan extracted Cannabis plant material;

(b) removing the supercritical fluid solvent system from the extract ofCannabis to provide a concentrate of Cannabis;

(c) contacting the extracted Cannabis plant material with a secondsupercritical fluid solvent system at a pressure between about 750 psiand 25,000 psi, and at a temperature between about −15° C. and 200° C.,to provide a second extract of Cannabis and a second extracted Cannabisplant material;

(d) removing the second supercritical fluid solvent system from thesecond extract of Cannabis to provide a second concentrate of Cannabis;

(e) contacting the second extracted Cannabis plant material with a thirdsupercritical fluid solvent system at a pressure between about 750 psiand 25,000 psi, and at a temperature between about −15° C. and 200° C.,to provide a third extract of Cannabis and a third extracted Cannabisplant material; and

(f) optionally removing the third supercritical fluid solvent systemfrom the third extract of Cannabis to provide a third concentrate ofCannabis.

[4.] A process for obtaining an extract of Cannabis, the processincluding:A process for obtaining an extract of Cannabis, the process including:

(a) contacting Cannabis with a supercritical fluid solvent system at apressure between about 750 psi and 25,000 psi, and at a temperaturebetween about −15° C. and 200° C., to provide an extract of Cannabis andan extracted Cannabis plant material;

(b) removing the supercritical fluid solvent system from the extract ofCannabis to provide a concentrate of Cannabis;

(c) contacting the extracted Cannabis plant material with a secondsupercritical fluid solvent system at a pressure between about 750 psiand 25,000 psi, and at a temperature between about −15° C. and 200° C.,to provide a second extract of Cannabis and a second extracted Cannabisplant material;

(d) removing the second supercritical fluid solvent system from thesecond extract of Cannabis to provide a second concentrate of Cannabis;

(e) contacting the second extracted Cannabis plant material with a thirdsupercritical fluid solvent system at a pressure between about 750 psiand 25,000 psi, and at a temperature between about −15° C. and 200° C.,to provide a third extract of Cannabis and a third extracted Cannabisplant material;

(f) removing the third supercritical fluid solvent system from the thirdextract of Cannabis to provide a third concentrate of Cannabis;

(g) contacting the third extracted Cannabis plant material with a fourthsupercritical fluid solvent system at a pressure between about 750 psiand 25,000 psi, and at a temperature between about −15° C. and 200° C.,to provide a fourth extract of Cannabis and a fourth extracted Cannabisplant material; and

(h) optionally removing the fourth supercritical fluid solvent systemfrom the fourth extract of Cannabis to provide a fourth concentrate ofCannabis.

[5.] A process for obtaining a concentrate of Cannabis, the processincluding:

(a) contacting Cannabis plant material with a supercritical fluidsolvent system, at a pressure between about 750 psi and 25,000 psi, andat a temperature between about −15° C. and 200° C., to provide anextract of Cannabis; and

(b) removing the supercritical fluid solvent system from the extract;

wherein the (a) contacting of the Cannabis plant material with thesupercritical fluid solvent system and the (b) removing thesupercritical fluid solvent system, is carried out multiple times, suchthat the process is a fractional supercritical fluid extraction;

wherein each contacting of the Cannabis plant material with asupercritical fluid solvent system independently occurs at a pressurebetween about 750 psi and 25,000 psi, and independently occurs at atemperature between about −15° C. and 200° C.

[6.] The process of any one of embodiments [1]-[5], wherein the Cannabisplant material is fresh, having been harvested within the past 10 days.[7.] The process of any one of embodiments [1]-[6], wherein thesupercritical fluid solvent system is removed from the extract ofCannabis, to provide the concentrate of Cannabis.[8.] The process of any one of embodiments [1]-[6], wherein the Cannabisplant material is dried, having a moisture content of less than about 10wt. %.[9.] The process of any one of embodiments [1]-[6], wherein the Cannabisplant material is dried, having a moisture content of less than about 5wt. %.[10.] The process of any one of embodiments [1]-[6], wherein theCannabis plant material is dried, having a moisture content of less thanabout 1 wt. %.[11.] The process of any one of embodiments [1]-[10], wherein theCannabis plant material is a physical portion of a Cannabis plant.[12.] The process of any one of embodiments [1]-[11], wherein theCannabis plant material is a leaf, bud, trichome, seed, or anycombination thereof, of a Cannabis plant.[13.] The process of any one of embodiments [1]-[12], wherein theCannabis plant comprises at least one of Cannabis sativa L., Cannabisindica Lam., and Cannabis ruderalis Janisch.[14.] The process of any one of embodiments [1]-[13], wherein eachpressure is independently between about 750 psi and 25,000 psi.[15.] The process of any one of embodiments [1]-[14], wherein any one ormore pressures is independently between about 750 psi and 1,500 psi.[16.] The process of any one of embodiments [1]-[15], wherein one ormore pressures is independently between about 1,500 psi and 4,000 psi.[17.] The process of any one of embodiments [1]-[16], wherein one ormore pressures is independently between about 4,000 psi and 25,000 psi.[18.] The process of any one of embodiments [1]-[17], wherein eachpressure is independently selected from (i) 750-4,000 psi, (ii)4,000-7,000 psi, and (iii) 7,000-25,000 psi.[19.] The process of any one of embodiments [1]-[17], wherein eachfractional supercritical fluid extraction is carried out at a differentrange of pressure, each selected from (i) 750-4,000 psi, (ii)4,000-7,000 psi, and (iii) 7,000-25,000 psi.[20.] The process of any one of embodiments [1]-[19], wherein eachtemperature is independently between about −15° C. and 200° C.[21.] The process of any one of embodiments [1]-[20], wherein any one ormore temperatures is independently between about 25° C. and 60° C.[22.] The process of any one of embodiments [1]-[21], wherein any one ormore temperatures is independently between about 60° C. and 110° C.[23.] The process of any one of embodiments [1]-[22], wherein any one ormore temperatures is independently between about 110° C. and 200° C.[24.] The process of any one of embodiments [1]-[23], wherein eachtemperature is independently selected from (i) −15-70° C., (ii) 70-100°C., and (iii) 100-200° C.[25.] The process of any one of embodiments [1]-[24], wherein eachfractional supercritical fluid extraction is carried out at a differentrange of temperature, each selected from (i) −15-70° C., (ii) 70-100°C., and (iii) 100-200° C.[26.] The process of any one of embodiments [1]-[25], wherein eachsupercritical fluid solvent system is independently:

(i) a polar aprotic supercritical fluid solvent system,

(ii) a polar protic supercritical fluid solvent system,

(iii) a nonpolar aprotic supercritical fluid solvent system, or

(iv) a nonpolar protic supercritical fluid solvent system.

[27.] The process of embodiment [25], wherein the selection of eachsupercritical fluid solvent system is mutually exclusive of all othersupercritical fluid solvent systems, regarding the designation of thecombination of polarity and proticity.[28.] The process of embodiment [25], wherein the selection of eachsupercritical fluid solvent system is the same to all othersupercritical fluid solvent systems, regarding the designation of thecombination of polarity and proticity.[29.] The process of any one of embodiments [1]-[25], wherein eachfractional supercritical fluid extraction is independently carried outemploying a supercritical fluid solvent system which is: (i) polaraprotic, (ii) polar protic, (iii) nonpolar aprotic, or (iv) nonpolarprotic.[30.] The process of any one of embodiments [1]-[25], wherein eachfractional supercritical fluid extraction is carried out with adifferent supercritical fluid solvent system, each selected from: (i)polar aprotic, (ii) polar protic, (iii) nonpolar aprotic, and (iv)nonpolar protic.[31.] The process of any one of embodiments [1]-[25], wherein eachsupercritical fluid solvent system includes at least one of:

-   -   carbon dioxide (CO₂),    -   hydrogen (H₂),    -   neon (Ne),    -   nitrogen (N₂),    -   argon (Ar),    -   methane (CH₄),    -   ethane (CH₃CH₃),    -   propane (CH₃CH₂CH₃),    -   ammonia (NH₃),    -   water (H₂O),    -   xenon (Xe),    -   methanol,    -   ethanol,    -   1-propanol,    -   2-propanol,    -   1-hexanol,    -   2-methoxy ethanol,    -   tetrahydrofuran (THF),    -   1,4-dioxane,    -   acetonitrile,    -   methylene chloride,    -   dichloroethane,    -   chloroform,    -   ethyl acetate,    -   propylene carbonate,    -   N,N-dimethylaceamide,    -   dimethyl sulfoxide (DMSO),    -   formic acid,    -   carbon disulfide,    -   acetone,    -   toluene,    -   hexanes,    -   pentanes,    -   trifluoromethane (Freon® 23),    -   nitrous oxide (N₂O),    -   sulfur hexafluroide (SF₆),    -   butane (n-C₄H₁₀),    -   isobutane (i-C₄H₁₀),    -   ethyl ether ((C₂H₅)₂O),    -   benzotrifluoride (C₆H₅CF₃),    -   (p-chlorophenyl)trifluoromethane (ClC₆H₄CF₃),    -   chlorofluorocarbon (CFC),    -   hydrofluorocarbon (HFA), and    -   HFA-134a (1,1,1,2-tetrafluoroethane).        [32.] The process of any one of embodiments [1]-[25], wherein        each supercritical fluid solvent system includes carbon dioxide        (CO₂) and at least one of:    -   hydrogen (H₂),    -   neon (Ne),    -   nitrogen (N₂),    -   argon (Ar),    -   methane (CH₄),    -   ethane (CH₃CH₃),    -   propane (CH₃CH₂CH₃),    -   ammonia (NH₃),    -   water (H₂O),    -   xenon (Xe),    -   methanol,    -   ethanol,    -   1-propanol,    -   2-propanol,    -   1-hexanol,    -   2-methoxy ethanol,    -   tetrahydrofuran (THF),    -   1,4-dioxane,    -   acetonitrile,    -   methylene chloride,    -   dichloroethane,    -   chloroform,    -   ethyl acetate,    -   propylene carbonate,    -   N,N-dimethylaceamide,    -   dimethyl sulfoxide (DMSO),    -   formic acid,    -   carbon disulfide,    -   acetone,    -   toluene,    -   hexanes,    -   pentanes,    -   trifluoromethane (Freon® 23),    -   nitrous oxide (N₂O),    -   sulfur hexafluroide (SF₆),    -   butane (n-C₄H₁₀),    -   isobutane (i-C₄H₁₀),    -   ethyl ether ((C₂H₅)₂O),    -   benzotrifluoride (C₆H₅CF₃),    -   (p-chlorophenyl)trifluoromethane (ClC₆H₄CF₃),    -   chlorofluorocarbon (CFC),    -   hydrofluorocarbon (HFA), and    -   HFA-134a (1,1,1,2-tetrafluoroethane).        [33.] The process of any one of embodiments [1]-[32], wherein        the extract of Cannabis comprises an extract of at least one of        kief and hashish.        [34.] The process of any one of embodiments [1]-[33], wherein        any one or more extract of Cannabis comprises a concentrate        comprising at least one of cannabinoids, terpenoids, and        flavonoids.        [35.] The process of any one of embodiments [1]-[34], wherein        any one or more extract of Cannabis comprises at least one of:

cannabinol (CBN),

cannabinolic acid (CBNA),

Δ(9)-tetrahydrocannabinol (Δ(9)-THC),

Δ(9)-tetrahydrocannabinolic acid (Δ(9)-THCA),

Δ(9)-cannabidiol (Δ(9)-CBD),

Δ(9)-tetrahydrocannabidiolic acid (Δ(9)-CBDA),

Δ(8)-tetrahydrocannabinol (Δ(8)-THC),

Δ(8)-tetrahydrocannabinolic acid (Δ(8)-THCA),

Δ(8)-tetrahydrocannabidiol (Δ(8)-CBD),

Δ(8)-tetrahydrocannabidiolic acid (Δ(8)-CBDA),

Δ(9)-tetrahydrocannabivarin (Δ(9)-THV),

cannabigerol (CBG),

cannabigerolic acid (CBGA),

cannabichromene (CBC),

cannabichromenic acid (CBCA),

cannabicyclol (CBL),

cannabicyclolic acid (CBLA),

β-caryophyllene epoxide,

mentha-1,8(9)-dien-5-ol,

pulegone,

limonene,

limonene oxide,

α-terpinene,

terpinen-4-ol,

carvacrol,

carvone,

1,8-cineole,

p-cymene,

fenchone,

pulegone-1,2epoxide,

β-myrcene,

cannaflavin A, and

cannaflavin B.

[36.] The process of any one of embodiments [1]-[35], wherein any one ormore extract or concentrate of Cannabis, relative to the Cannabis plantmaterial, is at least partially purified from at least one of terpenes,alkaloids, hemp oil, and cannabinoid acids.[37.] The process of any one of embodiments [1]-[24], wherein any one ormore extract or concentrate of Cannabis, relative to the Cannabis plantmaterial, is at least partially purified from terpenes.[38.] The process of any one of embodiments [1]-[37], which is afractional supercritical fluid extraction, such that the (a) contactingof Cannabis plant material with the supercritical fluid solvent system,and the (b) removing the supercritical fluid solvent system to provide aconcentrate of Cannabis, is carried out multiple times.[39.] The process of any one of embodiments [1]-[37], which is afractional supercritical fluid extraction, such that the (a) contactingCannabis plant material with the supercritical fluid solvent system andthe (b) removing the supercritical fluid solvent system to provide aconcentrate of Cannabis, is carried out multiple times, each pressureindependently between about 750 psi and 25,000 psi, each temperatureindependently between about −15° C. and 200° C., and each solvent systemindependently selected.[40.] The process of any one of embodiments [1]-[37], which is afractional supercritical fluid extraction, such that after removing thesupercritical fluid solvent system to provide a concentrate of Cannabis,the extracted Cannabis plant material is contacted with a subsequentsupercritical fluid solvent system at a pressure between about 750 psiand 25,000 psi, and at a temperature between about −15° C. and 200° C.,to provide a subsequent extract of Cannabis, and the subsequentsupercritical fluid solvent system is removed from the subsequentextract to provide a subsequent concentrate of Cannabis.[41.] The process of any one of embodiments [1]-[40], further comprisingcombining any two or more of the multiple extracts or concentrates ofCannabis.[42.] The process of any one of embodiments [1]-[41], further comprisingdiscarding any one or more of the multiple extracts or concentrates ofCannabis.[43.] The process of any one of embodiments [1]-[42], further comprisingpurifying any one or more extracts or concentrates of Cannabis, orcombination thereof.[44.] The process of any one of embodiments [1]-[43], further comprisingpurifying any one or more extracts or concentrates of Cannabis, orcombination thereof, employing at least one of chromatography,adsorption, crystallization, distillation, liquid-liquid extraction,filtration, fractional distillation, precipitation, recrystallization,and sublimation.[45.] An extract or concentrate of Cannabis obtained by the process ofany one of embodiments [1]-[44].[46.] A pharmaceutical dosage form that includes a Cannabis concentrateincluding at least one of cannabinol (CBN); cannabinolic acid (CBNA);Δ(9)-tetrahydrocannabinol (Δ(9)-THC); Δ(9)-tetrahydrocannabinolic acid(Δ(9)-THCA); Δ(9)-cannabidiol (Δ(9)-CBD); Δ(9)-tetrahydrocannabidiolicacid (Δ(9)-CBDA); Δ(8)-tetrahydrocannabinol (Δ(8)-THC);Δ(8)-tetrahydrocannabinolic acid (Δ(8)-THCA); Δ(8)-tetrahydrocannabidiol(Δ(8)-CBD); Δ(8)-tetrahydrocannabidiolic acid (Δ(8)-CBDA);Δ(9)-tetrahydrocannabivarin (Δ(9)-THV); cannabigerol (CBG);cannabigerolic acid (CBGA); cannabichromene (CBC); cannabichromenic acid(CBCA); cannabicyclol (CBL); cannabicyclolic acid (CBLA);β-caryophyllene epoxide; mentha-1,8(9)-dien-5-ol; pulegone; limonene;limonene oxide; α-terpinene; terpinen-4-ol; carvacrol; carvone;1,8-cineole; p-cymene; fenchone; pulegone-1,2epoxide; β-myrcene;cannaflavin A; and cannaflavin B.[47.] The pharmaceutical dosage form of embodiment [46], whereincompared to the Cannabis plant material, the Cannabis concentrate isenriched in at least one of cannabinol (CBN); cannabinolic acid (CBNA);Δ(9)-tetrahydrocannabinol (Δ(9)-THC); Δ(9)-tetrahydrocannabinolic acid(Δ(9)-THCA); Δ(9)-cannabidiol (Δ(9)-CBD); Δ(9)-tetrahydrocannabidiolicacid (Δ(9)-CBDA); Δ(8)-tetrahydrocannabinol (Δ(8)-THC);Δ(8)-tetrahydrocannabinolic acid (Δ(8)-THCA); Δ(8)-tetrahydrocannabidiol(Δ(8)-CBD); Δ(8)-tetrahydrocannabidiolic acid (Δ(8)-CBDA);Δ(9)-tetrahydrocannabivarin (Δ(9)-THV); cannabigerol (CBG);cannabigerolic acid (CBGA); cannabichromene (CBC); cannabichromenic acid(CBCA); cannabicyclol (CBL); cannabicyclolic acid (CBLA);β-caryophyllene epoxide; mentha-1,8(9)-dien-5-ol; pulegone; limonene;limonene oxide; α-terpinene; terpinen-4-ol; carvacrol; carvone;1,8-cineole; p-cymene; fenchone; pulegone-1,2epoxide; β-myrcene;cannaflavin A; and cannaflavin B.[48.] The pharmaceutical dosage form of any one of embodiments[46]-[47], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a higher relative concentration of cannabinol(CBN).[49.] The pharmaceutical dosage form of any one of embodiments[46]-[47], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a lower relative concentration of cannabinol (CBN).[50.] The pharmaceutical dosage form of any one of embodiments[46]-[49], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a higher relative concentration of cannabinolicacid (CBNA).[51.] The pharmaceutical dosage form of any one of embodiments[46]-[49], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a lower relative concentration of cannabinolic acid(CBNA).[52.] The pharmaceutical dosage form of any one of embodiments[46]-[51], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a higher relative concentration ofΔ(9)-tetrahydrocannabinol (Δ(9)-THC).[53.] The pharmaceutical dosage form of any one of embodiments[46]-[51], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a lower relative concentration ofΔ(9)-tetrahydrocannabinol (Δ(9)-THC).[54.] The pharmaceutical dosage form of any one of embodiments[46]-[53], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a higher relative concentration ofΔ(9)-tetrahydrocannabinolic acid (Δ(9)-THCA).[55.] The pharmaceutical dosage form of any one of embodiments[46]-[53], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a lower relative concentration ofΔ(9)-tetrahydrocannabinolic acid (Δ(9)-THCA).[56.] The pharmaceutical dosage form of any one of embodiments[46]-[55], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a higher relative concentration of Δ(9)-cannabidiol(Δ(9)-CBD).[57.] The pharmaceutical dosage form of any one of embodiments[46]-[55], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a lower relative concentration of Δ(9)-cannabidiol(Δ(9)-CBD).[58.] The pharmaceutical dosage form of any one of embodiments[46]-[57], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a higher relative concentration ofΔ(9)-tetrahydrocannabidiolic acid (Δ(9)-CBDA).[59.] The pharmaceutical dosage form of any one of embodiments[46]-[57], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a lower relative concentration ofΔ(9)-tetrahydrocannabidiolic acid (Δ(9)-CBDA).[60.] The pharmaceutical dosage form of any one of embodiments[46]-[59], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a higher relative concentration ofΔ(8)-tetrahydrocannabinol (Δ(8)-THC).[61.] The pharmaceutical dosage form of any one of embodiments[46]-[59], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a lower relative concentration ofΔ(8)-tetrahydrocannabinol (Δ(8)-THC).[62.] The pharmaceutical dosage form of any one of embodiments[46]-[61], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a higher relative concentration ofΔ(8)-tetrahydrocannabinolic acid (Δ(8)-THCA).[63.] The pharmaceutical dosage form of any one of embodiments[46]-[61], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a lower relative concentration ofΔ(8)-tetrahydrocannabinolic acid (Δ(8)-THCA).[64.] The pharmaceutical dosage form of any one of embodiments[46]-[63], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a higher relative concentration ofΔ(8)-tetrahydrocannabidiol (Δ(8)-CBD).[65.] The pharmaceutical dosage form of any one of embodiments[46]-[63], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a lower relative concentration ofΔ(8)-tetrahydrocannabidiol (Δ(8)-CBD).[66.] The pharmaceutical dosage form of any one of embodiments[46]-[65], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a higher relative concentration ofΔ(8)-tetrahydrocannabidiolic acid (Δ(8)-CBDA).[67.] The pharmaceutical dosage form of any one of embodiments[46]-[65], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a lower relative concentration ofΔ(8)-tetrahydrocannabidiolic acid (Δ(8)-CBDA).[68.] The pharmaceutical dosage form of any one of embodiments[46]-[67], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a higher relative concentration ofΔ(9)-tetrahydrocannabivarin (Δ(9)-THV).[69.] The pharmaceutical dosage form of any one of embodiments[46]-[67], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a lower relative concentration ofΔ(9)-tetrahydrocannabivarin (Δ(9)-THV).[70.] The pharmaceutical dosage form of any one of embodiments[46]-[69], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a higher relative concentration of cannabigerol(CBG).[71.] The pharmaceutical dosage form of any one of embodiments[46]-[69], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a lower relative concentration of cannabigerol(CBG).[72.] The pharmaceutical dosage form of any one of embodiments[46]-[71], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a higher relative concentration of cannabigerolicacid (CBGA).[73.] The pharmaceutical dosage form of any one of embodiments[46]-[71], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a lower relative concentration of cannabigerolicacid (CBGA).[74.] The pharmaceutical dosage form of any one of embodiments[46]-[73], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a higher relative concentration of cannabichromene(CBC).[75.] The pharmaceutical dosage form of any one of embodiments[46]-[73], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a lower relative concentration of cannabichromene(CBC).[76.] The pharmaceutical dosage form of any one of embodiments[46]-[75], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a higher relative concentration of cannabichromenicacid (CBCA).[77.] The pharmaceutical dosage form of any one of embodiments[46]-[75], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a lower relative concentration of cannabichromenicacid (CBCA).[78.] The pharmaceutical dosage form of any one of embodiments[46]-[77], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a higher relative concentration of cannabicyclol(CBL).[79.] The pharmaceutical dosage form of any one of embodiments[46]-[77], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a lower relative concentration of cannabicyclol(CBL).[80.] The pharmaceutical dosage form of any one of embodiments[46]-[79], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a higher relative concentration of cannabicyclolicacid (CBLA).[81.] The pharmaceutical dosage form of any one of embodiments[46]-[79], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a lower relative concentration of cannabicyclolicacid (CBLA).[82.] The pharmaceutical dosage form of any one of embodiments[46]-[81], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a higher relative concentration of β-caryophylleneepoxide.[83.] The pharmaceutical dosage form of any one of embodiments[46]-[81], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a lower relative concentration of β-caryophylleneepoxide.[84.] The pharmaceutical dosage form of any one of embodiments[46]-[83], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a higher relative concentration ofmentha-1,8(9)-dien-5-ol.[85.] The pharmaceutical dosage form of any one of embodiments[46]-[83], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a lower relative concentration ofmentha-1,8(9)-dien-5-ol.[86.] The pharmaceutical dosage form of any one of embodiments[46]-[85], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a higher relative concentration of pulegone.[87.] The pharmaceutical dosage form of any one of embodiments[46]-[85], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a lower relative concentration of pulegone.[88.] The pharmaceutical dosage form of any one of embodiments[46]-[87], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a higher relative concentration of limonene.[89.] The pharmaceutical dosage form of any one of embodiments[46]-[87], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a lower relative concentration of limonene.[90.] The pharmaceutical dosage form of any one of embodiments[46]-[89], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a higher relative concentration of limonene oxide.[91.] The pharmaceutical dosage form of any one of embodiments[46]-[89], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a lower relative concentration of limonene oxide.[92.] The pharmaceutical dosage form of any one of embodiments[46]-[91], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a higher relative concentration of α-terpinene.[93.] The pharmaceutical dosage form of any one of embodiments[46]-[91], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a lower relative concentration of α-terpinene.[94.] The pharmaceutical dosage form of any one of embodiments[46]-[93], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a higher relative concentration of terpinen-4-ol.[95.] The pharmaceutical dosage form of any one of embodiments[46]-[93], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a lower relative concentration of terpinen-4-ol.[96.] The pharmaceutical dosage form of any one of embodiments[46]-[95], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a higher relative concentration of carvacrol.[97.] The pharmaceutical dosage form of any one of embodiments[46]-[95], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a lower relative concentration of carvacrol.[98.] The pharmaceutical dosage form of any one of embodiments[46]-[97], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a higher relative concentration of carvone.[99.] The pharmaceutical dosage form of any one of embodiments[46]-[97], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a lower relative concentration of carvone.[100.] The pharmaceutical dosage form of any one of embodiments[46]-[99], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a higher relative concentration of 1,8-cineole.[101.] The pharmaceutical dosage form of any one of embodiments[46]-[99], wherein compared to the Cannabis plant material, the Cannabisconcentrate includes a lower relative concentration of 1,8-cineole.[102.] The pharmaceutical dosage form of any one of embodiments[46]-[101], wherein compared to the Cannabis plant material, theCannabis concentrate includes a higher relative concentration ofp-cymene.[103.] The pharmaceutical dosage form of any one of embodiments[46]-[101], wherein compared to the Cannabis plant material, theCannabis concentrate includes a lower relative concentration ofp-cymene.[104.] The pharmaceutical dosage form of any one of embodiments[46]-[103], wherein compared to the Cannabis plant material, theCannabis concentrate includes a higher relative concentration offenchone.[105.] The pharmaceutical dosage form of any one of embodiments[46]-[103], wherein compared to the Cannabis plant material, theCannabis concentrate includes a lower relative concentration offenchone.[106.] The pharmaceutical dosage form of any one of embodiments[46]-[105], wherein compared to the Cannabis plant material, theCannabis concentrate includes a higher relative concentration ofpulegone-1,2epoxide.[107.] The pharmaceutical dosage form of any one of embodiments[46]-[105], wherein compared to the Cannabis plant material, theCannabis concentrate includes a lower relative concentration ofpulegone-1,2epoxide.[108.] The pharmaceutical dosage form of any one of embodiments[46]-[107], wherein compared to the Cannabis plant material, theCannabis concentrate includes a higher relative concentration ofβ-myrcene.[109.] The pharmaceutical dosage form of any one of embodiments[46]-[107], wherein compared to the Cannabis plant material, theCannabis concentrate includes a lower relative concentration ofβ-myrcene.[110.] The pharmaceutical dosage form of any one of embodiments[46]-[109], wherein compared to the Cannabis plant material, theCannabis concentrate includes a higher relative concentration ofcannaflavin A.[111.] The pharmaceutical dosage form of any one of embodiments[46]-[109], wherein compared to the Cannabis plant material, theCannabis concentrate includes a lower relative concentration ofcannaflavin A.[112.] The pharmaceutical dosage form of any one of embodiments[46]-[111], wherein compared to the Cannabis plant material, theCannabis concentrate includes a higher relative concentration ofcannaflavin B.[113.] The pharmaceutical dosage form of any one of embodiments[46]-[111], wherein compared to the Cannabis plant material, theCannabis concentrate includes a lower relative concentration ofcannaflavin B.[114.] The pharmaceutical dosage form of embodiment [46], whereincompared to the Cannabis plant material, the Cannabis concentrateincludes a higher relative concentration of each of cannabinol (CBN);cannabinolic acid (CBNA); Δ(9)-tetrahydrocannabinol (Δ(9)-THC);Δ(9)-tetrahydrocannabinolic acid (Δ(9)-THCA); Δ(9)-cannabidiol(Δ(9)-CBD); Δ(9)-tetrahydrocannabidiolic acid (Δ(9)-CBDA);Δ(8)-tetrahydrocannabinol (Δ(8)-THC); Δ(8)-tetrahydrocannabinolic acid(Δ(8)-THCA); Δ(8)-tetrahydrocannabidiol (Δ(8)-CBD);Δ(8)-tetrahydrocannabidiolic acid (Δ(8)-CBDA);Δ(9)-tetrahydrocannabivarin (Δ(9)-THV); cannabigerol (CBG);cannabigerolic acid (CBGA); cannabichromene (CBC); cannabichromenic acid(CBCA); cannabicyclol (CBL); cannabicyclolic acid (CBLA);β-caryophyllene epoxide; mentha-1,8(9)-dien-5-ol; pulegone; limonene;limonene oxide; α-terpinene; terpinen-4-ol; carvacrol; carvone;1,8-cineole; p-cymene; fenchone; pulegone-1,2epoxide; β-myrcene;cannaflavin A; and cannaflavin B.[115.] A pharmaceutical dosage form comprising a supercritical fluidextract or concentrate of Cannabis.[116.] A pharmaceutical dosage form comprising a fractionalsupercritical fluid extract or concentrate of Cannabis.[117.] The pharmaceutical dosage form of any one of embodiments[46]-[116], wherein the Cannabis concentrate is obtained by the processof any one of embodiments [1]-[44].[118.] A pharmaceutical dosage form comprising the extract orconcentrate of embodiment [45].[119.] The pharmaceutical dosage form of any one of embodiments[46]-[118], which is suitable for oral delivery, ophthalmic delivery,nasal delivery, or dermal delivery.[120.] The pharmaceutical dosage form of any one of embodiments[46]-[119], which is in the form of a pill, osmotic delivery system,elixir, emulsion, hydrogel, suspension, syrup, capsule, tablet, orallydissolving tablet (ODT), gel capsule, thin film, oral thin film (OTF),adhesive topical patch, lollipop, lozenge, chewing gum, dry powderinhaler (DPI), vaporizer, nebulizer, metered dose inhaler (MDI),ointment, transdermal patch, intradermal implant, subcutaneous implant,or transdermal implant.[121.] The pharmaceutical dosage form of any one of embodiments[46]-[120], which is in the form of a transdermal patch.[122.] The pharmaceutical dosage form of any one of embodiments[46]-[120], which is in the form of a thin film.[123.] The pharmaceutical dosage form of any one of embodiments[46]-[120], which is in the form of an oral thin film (OTF).[124.] The pharmaceutical dosage form of any one of embodiments[46]-[120], which is in the form of an orally dissolving tablet (ODT).[125.] A method of treating a mammal afflicted with a disease ordisorder, the method including administering to a mammal in need of suchtreatment, the pharmaceutical dosage form of any one of embodiments[46]-[124], in an amount and for a period of time, effective to treatthe disease or disorder.[126.] The method of embodiment [125], wherein the disease or disorderincludes any one or more of:

neuroinflammation,

epilepsy,

Alzheimer's disease,

oxidative injury,

vomiting and nausea,

anxiety,

anorexia,

arthritis,

schizophrenia,

multiple sclerosis,

joint inflammation,

joint pain,

symptoms associated with AIDS,

chronic pain,

acute pain,

anxiety,

neuropathic pain and spasticity,

inflammatory bowel diseases (IBD),

tumour neovascularization,

tumor growth,

cancer,

glaucoma,

muscle spasms,

severe pain,

severe nausea,

cachexia or dramatic weight loss and muscle atrophy (wasting syndrome)

cancer cell migration,

cancer cell adhesion,

cancer cell invasion, and

cancer cell metastasization.

[127.] The method of any one of embodiments [125]-[126], wherein thepharmaceutical dosage form provides for the time release of the extractor concentrate of Cannabis.[128.] The method of any one of embodiments [125]-[126], wherein thepharmaceutical dosage form provides for the controlled release of theextract or concentrate of Cannabis.[129.] The method of any one of embodiments [125]-[126], wherein thepharmaceutical dosage form provides for the continuous release of theextract or concentrate of Cannabis.[130.] The method of any one of embodiments [125]-[126], wherein thepharmaceutical dosage form provides for the sustained release of theextract or concentrate of Cannabis.[131.] The method of any one of embodiments [125]-[126], wherein thepharmaceutical dosage form provides for the modified release of theextract or concentrate of Cannabis.[132.] The method of any one of embodiments [125]-[126], wherein thepharmaceutical dosage form provides for the immediate release of theextract or concentrate of Cannabis.[133.] The method of any one of embodiments [125]-[126], wherein thepharmaceutical dosage form provides for the extended release of theextract or concentrate of Cannabis.[134.] The method of any one of embodiments [125]-[133], wherein thepharmaceutical dosage form provides for the release of the extract orconcentrate of Cannabis, over a period of time of about 1 hour to about24 hours.[135.] The method of any one of embodiments [125]-[133], wherein thepharmaceutical dosage form provides for the release of the extract orconcentrate of Cannabis, over a period of time of about 4 hours to about24 hours.[136.] The method of any one of embodiments [125]-[133], wherein thepharmaceutical dosage form provides for the release of the extract orconcentrate of Cannabis, over a period of time of about 6 hours to about24 hours.[137.] The method of any one of embodiments [125]-[133], wherein thepharmaceutical dosage form provides for the release of the extract orconcentrate of Cannabis, over a period of time of about 8 hours to about24 hours.[138.] The method of any one of embodiments [125]-[133], wherein thepharmaceutical dosage form provides for the release of the extract orconcentrate of Cannabis, over a period of time of about 1 hour to about12 hours.[139.] The method of any one of embodiments [125]-[133], wherein thepharmaceutical dosage form provides for the release of the extract orconcentrate of Cannabis, over a period of time of about 2 hours to about12 hours.[140.] The method of any one of embodiments [125]-[133], wherein thepharmaceutical dosage form provides for the release of the extract orconcentrate of Cannabis, over a period of time of about 4 hours to about12 hours.[141.] The method of any one of embodiments [125]-[133], wherein thepharmaceutical dosage form provides for the release of the extract orconcentrate of Cannabis, over a period of time of about 6 hours to about12 hours.[142.] The method of any one of embodiments [125]-[133], wherein thepharmaceutical dosage form provides for the release of the extract orconcentrate of Cannabis, over a period of time of about 1 hour to about4 hours.[143.] The method of any one of embodiments [125]-[133], wherein thepharmaceutical dosage form provides for the release of the extract orconcentrate of Cannabis, over a period of time of about 1 hour to about2 hours.[144.] The method of any one of embodiments [125]-[143], wherein thepharmaceutical dosage form is administered up to about 8 times per day.[145.] The method of any one of embodiments [125]-[143], wherein thepharmaceutical dosage form is administered about 1-4 times per day.[146.] The method of any one of embodiments [125]-[143], wherein thepharmaceutical dosage form is administered in a single daily dosage, 1time per day.

1. (canceled)
 2. An oral thin film (OTF) suitable for oral delivery, theOTF comprising: one or more mucoadhesive agents; and a cannabisconcentrate; wherein, the cannabis concentrate is obtained from afractional supercritical fluid extraction (FSFE) of cannabis plantmaterial; relative to the cannabis plant material, the cannabisconcentrate is enriched with cannabidiol (CBD); and relative to thecannabis plant material, the cannabis concentrate contains a lowerconcentration of tetrahydrocannabinol (THC).
 3. The oral thin film (OTF)of claim 1, wherein relative to the cannabis plant material, thecannabis concentrate further contains a lower concentration of at leastone of (i)-(vi): (i) cannabinol (CBN), (ii) alkaloids, (iii) terpenes,(iv) terpenoids, (v) cannabinoid acids, and (vi) hemp oil.
 4. The oralthin film (OTF) of claim 1, wherein relative to the cannabis plantmaterial, the cannabis concentrate is enriched with cannabidiol (CBD),such that the cannabis concentrate contains at least about a 10% higherconcentration of cannabidiol (CBD).
 5. The oral thin film (OTF) of claim1, wherein the cannabis concentrate is obtained from a fractionalsupercritical fluid extraction (FSFE) of cannabis plant material thatcomprises: (a) contacting cannabis plant material with a firstsupercritical fluid solvent system at a pressure between about 750 psiand 25,000 psi, and at a temperature between about −15° C. and 200° C.,to provide a first extract of cannabis and a first extracted cannabisplant material; (b) removing the first supercritical fluid solventsystem from the first extract of cannabis to provide a first concentrateof cannabis; (c) contacting the first extracted cannabis plant materialwith a second supercritical fluid solvent system at a pressure betweenabout 750 psi and 25,000 psi, and at a temperature between about −15° C.and 200° C., to provide a second extract of cannabis and a secondextracted cannabis plant material; and (d) removing the secondsupercritical fluid solvent system from the second extract of cannabisto provide a second concentrate of cannabis.
 6. The oral thin film (OTF)of claim 5, wherein the first fractional supercritical fluid extractionis carried out in a solvent system that comprises carbon dioxide (CO₂)and at least one of hydrogen (H₂), neon (Ne), nitrogen (N₂), argon (Ar),methane (CH₄), ethane (CH₃CH₃), propane (CH₃CH₂CH₃), ammonia (NH₃),water (H₂O), xenon (Xe), methanol, ethanol, 1-propanol, 2-propanol,1-hexanol, 2-methoxy ethanol, tetrahydrofuran (THF), 1,4-dioxane,acetonitrile, methylene chloride, dichloroethane, chloroform, ethylacetate, propylene carbonate, N,N-dimethylaceamide, dimethyl sulfoxide(DMSO), formic acid, carbon disulfide, acetone, toluene, hexanes,pentanes, trifluoromethane (Freon® 23), nitrous oxide (N₂O), sulfurhexafluroide (SF₆), butane (n-C₄H₁₀), isobutane (i-C₄H₁₀), ethyl ether((C₂H₅)₂O), benzotrifluoride (C₆H₅CF₃), (p-chlorophenyl)trifluoromethane(ClC₆H₄CF₃), chlorofluorocarbon (CFC), hydrofluorocarbon (HFA), andHFA-134a (1,1,1,2-tetrafluoroethane).
 7. The oral thin film (OTF) ofclaim 5, wherein the second fractional supercritical fluid extraction iscarried out in a solvent system that comprises carbon dioxide (CO₂) andat least one of hydrogen (H₂), neon (Ne), nitrogen (N₂), argon (Ar),methane (CH₄), ethane (CH₃CH₃), propane (CH₃CH₂CH₃), ammonia (NH₃),water (H₂O), xenon (Xe), methanol, ethanol, 1-propanol, 2-propanol,1-hexanol, 2-methoxy ethanol, tetrahydrofuran (THF), 1,4-dioxane,acetonitrile, methylene chloride, dichloroethane, chloroform, ethylacetate, propylene carbonate, N,N-dimethylaceamide, dimethyl sulfoxide(DMSO), formic acid, carbon disulfide, acetone, toluene, hexanes,pentanes, trifluoromethane (Freon® 23), nitrous oxide (N₂O), sulfurhexafluroide (SF₆), butane (n-C₄H₁₀), isobutane (i-C₄H₁₀), ethyl ether((C₂H₅)₂O), benzotrifluoride (C₆H₅CF₃), (p-chlorophenyl)trifluoromethane(ClC₆H₄CF₃), chlorofluorocarbon (CFC), hydrofluorocarbon (HFA), andHFA-134a (1,1,1,2-tetrafluoroethane).
 8. The oral thin film (OTF) ofclaim 5, wherein the contacting the cannabis plant material with thefirst supercritical fluid solvent system and the contacting the firstextracted cannabis plant material with the second supercritical fluidsolvent system are carried out: (a) at the same temperature anddifferent pressures; (b) at different temperatures and the samepressure; or (c) at different temperatures and different pressures. 9.The oral thin film (OTF) of claim 5, wherein the pressure employed incontacting cannabis plant material with the first supercritical fluidsolvent system is greater than the pressure employed in contacting thefirst extracted cannabis plant material with the second supercriticalfluid solvent system.
 10. The oral thin film (OTF) of claim 5, whereinthe pressure employed in contacting cannabis plant material with thefirst supercritical fluid solvent system is less than the pressureemployed in contacting the first extracted cannabis plant material withthe second supercritical fluid solvent system.
 11. The oral thin film(OTF) of claim 5, wherein the temperature employed in contactingcannabis plant material with the first supercritical fluid solventsystem is greater than the temperature employed in contacting the firstextracted cannabis plant material with the second supercritical fluidsolvent system.
 12. The oral thin film (OTF) of claim 5, wherein thetemperature employed in contacting cannabis plant material with thefirst supercritical fluid solvent system is less than the temperatureemployed in contacting the first extracted cannabis plant material withthe second supercritical fluid solvent system.
 13. The oral thin film(OTF) of claim 5, further comprising purifying the first concentrate ofcannabis employing at least one of chromatography, adsorption,crystallization, distillation, liquid-liquid extraction, filtration,fractional distillation, precipitation, recrystallization, andsublimation.
 14. The oral thin film (OTF) of claim 5, further comprisingpurifying the second concentrate of cannabis employing at least one ofchromatography, adsorption, crystallization, distillation, liquid-liquidextraction, filtration, fractional distillation, precipitation,recrystallization, and sublimation.
 15. The oral thin film (OTF) ofclaim 1, further comprising at least one of: one or more plasticizers;one or more sweetening agents; one or more saliva stimulating agents;one or more flavoring agents; one or more coloring agents; one or morestabilizing agents; one or more thickening agents; one or more bitterblockers; one or more dye, pigment, or coloring agents; and one or morepreservatives.
 16. The oral thin film (OTF) of claim 1, wherein themucoadhesive agent comprises a polymeric compound.
 17. The oral thinfilm (OTF) of claim 1, wherein the mucoadhesive agent comprises acellulose derivative, a natural gum, alginate, pectin, or combinationthereof.
 18. The oral thin film (OTF) of claim 1, wherein themucoadhesive agent comprises at least one of carboxymethyl cellulose,polyvinyl alcohol, polyvinyl pyrrolidone (povidone), sodium alginate,methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycols, carbopols, polycarbophils, carboxyvinylcopolymers, propylene glycol alginate, alginic acid, methyl methacrylatecopolymers, tragacanth gum, guar gum, karaya gum, ethylene vinylacetate, dimenthylpolysiloxanes, polyoxyalkylene block copolymers,pectin, chitosan, carrageenan, xanthan gum, gellan gum, locust bean gum,and hydroxyethylmethacrylate copolymers.
 19. The oral thin film (OTF) ofclaim 5, wherein the cannabis concentrate is obtained from thefractional supercritical fluid extraction (FSFE) of cannabis plantmaterial that further comprises: (e) contacting the second extractedcannabis plant material with a third supercritical fluid solvent systemat a pressure between about 750 psi and 25,000 psi, and at a temperaturebetween about −15° C. and 200° C., to provide a third extract ofcannabis and a third extracted cannabis plant material; and (f) removingthe third supercritical fluid solvent system from the third extract ofcannabis to provide a third concentrate of cannabis.
 20. An oral thinfilm (OTF) suitable for oral delivery, the OTF comprising: amucoadhesive agent comprising at least one of carboxymethyl cellulose,polyvinyl alcohol, polyvinyl pyrrolidone (povidone), sodium alginate,methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycols, carbopols, polycarbophils, carboxyvinylcopolymers, propylene glycol alginate, alginic acid, methyl methacrylatecopolymers, tragacanth gum, guar gum, karaya gum, ethylene vinylacetate, dimenthylpolysiloxanes, polyoxyalkylene block copolymers,pectin, chitosan, carrageenan, xanthan gum, gellan gum, locust bean gum,and hydroxyethylmethacrylate copolymers; and a cannabis concentrate, andat least one of (a)-(j): (a) one or more plasticizers, (b) one or moresweetening agents, (c) one or more saliva stimulating agents, (d) one ormore flavoring agents, (e) one or more coloring agents, (f) one or morestabilizing agents, (g) one or more thickening agents, (h) one or morebitter blockers, (i) one or more dye, pigment, or coloring agents, and(j) one or more preservatives; wherein, the cannabis concentrate isobtained from a fractional supercritical fluid extraction (FSFE) ofcannabis plant material, relative to the cannabis plant material, thecannabis concentrate is enriched with cannabidiol (CBD), such that thecannabis concentrate contains at least about a 10% higher concentrationof cannabidiol (CBD); relative to the cannabis plant material, thecannabis concentrate contains at least about a 10% lower concentrationof at least one of (i)-(vii): (i) cannabinol (CBN), (ii)tetrahydrocannabinol (THC), (iii) terpenes, (iv) terpenoids, (v)alkaloids, (vi) cannabinoid acids, and (vii) hemp oil.
 21. The oral thinfilm (OTF) of claim 20, wherein the cannabis concentrate is obtainedfrom a fractional supercritical fluid extraction (FSFE) of cannabisplant material that comprises: (a) contacting cannabis plant materialwith a first supercritical fluid solvent system at a pressure betweenabout 750 psi and 25,000 psi, and at a temperature between about −15° C.and 200° C., to provide a first extract of cannabis and a firstextracted cannabis plant material; (b) removing the first supercriticalfluid solvent system from the first extract of cannabis to provide afirst concentrate of cannabis; (c) contacting the first extractedcannabis plant material with a second supercritical fluid solvent systemat a pressure between about 750 psi and 25,000 psi, and at a temperaturebetween about −15° C. and 200° C., to provide a second extract ofcannabis and a second extracted cannabis plant material; and (d)removing the second supercritical fluid solvent system from the secondextract of cannabis to provide a second concentrate of cannabis; whereinthe contacting the cannabis plant material with the first supercriticalfluid solvent system and the contacting the first extracted cannabisplant material with the second supercritical fluid solvent system arecarried out: (i) at the same temperature and different pressures; (ii)at different temperatures and the same pressure; (iii) at differenttemperatures and different pressures; or (iv) with differentsupercritical fluid solvent systems.